Thienopyrazole derivative having PDE7 inhibitory activity

ABSTRACT

To provide thienopyrazole derivatives inhibiting PDE 7 selectively, and therefore, enhance cellular cAMP level. Consequently, the compound is useful for treating various kinds of disease such as allergic diseases, inflammatory diseases or immunologic diseases. The compound is thienopyrazole compound represented by the following formula (I): 
                         
[wherein, especially, R 1  is a cyclohexyl, a cycloheptyl group or a tetrahydropyranyl group; R 2  is methyl; R 3  is a hydrogen atom; and R 4  is a group: —CONR 5 R 6  (in which any one of R 5  and R 6  is a hydrogen atom)].

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 13/047,660,filed Mar. 14, 2011, which is a divisional of application Ser. No.11/630,757, filed May 29, 2008, which is a National Stage ofInternational Application No. PCT/JP2005/012208, filed Jul. 1, 2005,which claims the benefit of Japanese Patent Application No. 2004-195836,filed on Jul. 1, 2004, and which are incorporated by reference herein intheir entirety.

TECHNICAL FIELD

The present invention relates to thienopyrazole derivatives,pharmaceutically acceptable salts and solvates thereof, having selectivePDE 7 (phosphodiesterase VII) inhibiting effect. Further, the presentinvention relates to an intermediate compounds for preparing saidthienopyrazole derivatives and a process for producing them. Thesecompounds are effective compounds for treating various kinds of diseasessuch as allergic diseases, inflammatory diseases and immunologicaldiseases.

BACKGROUND ART

Cyclic AMP (cAMP) or cyclic GMP (cGMP), which is an intracellular secondmessenger substance, is decomposed and inactivated by phosphodiesterases(PDE 1 to PDE 11). The PDE 7 selectively decomposes cAMP, and ischaracterized as an enzyme which is not inhibited by rolipram. Rolipramis a selective inhibitor of PDE 4, which decomposes cAMP similarly.

It is suggested that PDE 7 plays an important role for activating Tcells (Beavo, et al., Science, 283, 848 (1999)), and is well known thatactivation of T-cell is concerned with the exacerbation of allergicdiseases, inflammatory diseases or immunological diseases. Thesediseases are for example bronchial asthma, chronic bronchitis, chronicobstructive pulmonary disease, allergic rhinitis, psoriasis, atopicdermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis,multiple sclerosis, systemic lupus erythematosus, inflammatory boweldisease, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn'sdisease, rejection reaction in transplantation, graft versus hostdisease (GVH disease), and restenosis after angioplasty [J. AllergyClin. Immunol., 2000 November; 106(5 Suppl.): S221-6; Am. J. Respir.Crit. Care Med., 1996 February; 153(2): 629-32; Am. J. Respir. Crit.Care Med., 1999 November; 160(5 Pt 2): S33-7; Clin. Exp. Allergy, 2000February; 30(2): 242-54; Hosp. Med., 1998 July; 59(7): 530-3; Int. Arch.Allergy Immunol., 1998 March; 115(3): 179-90; J. Immunol., 1991 Feb. 15;146(4): 1169-74; Osteoarthritis Cartilage, 1999 July; 7(4): 401-2;Rheum. Dis. Clin. North Am., 2001 May; 27(2): 317-34; J. Autoimmun.,2001 May; 16(3): 187-92; Curr. Rheumatol. Rep., 2000 February; 2(1):24-31; Trends Immunol., 2001 January; 22(1): 21-6; Curr. Opin. Immunol.,2000 August; 12(4): 403-8; Diabetes Care, 2001 September; 24(9): 1661-7;J. Neuroimmunol., 2000 Nov. 1; 111(1-2): 224-8; Curr. Opin. Immunol.,1997 December; 9(6): 793-9; JAMA, 1999 Sep. 15; 282(11):1076-82; Semin.Cancer Biol., 1996 April; 7(2): 57-64; J. Interferon Cytokine Res., 2001April; 21(4): 219-21].

Therefore, it is considered that a compound having PDE 7 inhibitingeffect is useful for treating various kinds of diseases such as allergicdiseases, inflammatory diseases or immunological diseases concerned withT cells.

There has been proposed that many compounds selectively inhibit PDE 7.There can be mentioned the examples such as imidazopyridine derivatives(Patent Document 1), dihydropurine derivatives (Patent Document 2),pyrrole derivatives (Patent Document 3), benzothiopyranoimidazolonederivatives (Patent Document 4), heterocyclic compounds (Patent Document5; Patent Document 6), quinazoline and pyridopyrimidine derivatives(Patent Document 7), spiro tricyclic compounds (Patent Document 8),thiazole and oxathiazole derivatives (Patent Document 9), sulfonamidederivatives (Patent Document 10), heterobiarylsulfonamide derivatives(Patent Document 11), dihydroisoquinoline derivatives (Patent Document12), guanine derivatives (Non-Patent Document 1), benzothiadiazinederivatives and benzothienothiadiazine derivatives (Non-Patent Document2, and Non-Patent Document 3). However, no curative medicines having PDE7 inhibiting effect as main pharmacological mechanism have developed upto now.

Though some compounds having thienopyrazole skeleton have been known(Patent Documents 13-24; Non-Patent Documents 4-8), there is nosuggestion that these compounds have PDE 7 inhibiting effect. Further,the method for producing the thienopyrazole derivatives of the presentinvention has been reported (Non-Patent Documents 9-11); however, thesubstituents on the thienopyrazole skeleton are different from those ofthe present invention.

-   Patent Document 1: International Patent Publication WO 01/34,601-   Patent Document 2: International Patent Publication WO 00/68,203-   Patent Document 3: International Patent Publication WO 01/32,618-   Patent Document 4: DE Patent 19,950,647-   Patent Document 5: International Patent Publications WO 02/88,080-   Patent Document 6: International Patent Publications WO 02/87,513-   Patent Document 7: International Patent Publication WO 02/102,315-   Patent Document 8: International Patent Publication WO 02/74,754-   Patent Document 9: International Patent Publication WO 02/28,847-   Patent Document 10: International Patent Publication WO 01/98,274-   Patent Document 11: International Patent Publication WO 01/74,786-   Patent Document 12: International Patent Publication WO 02/40,450-   Patent Document 13: International Patent Publication WO 02/100,403-   Patent Document 14: International Patent Publication WO 02/79,146-   Patent Document 15: International Patent Publication WO 02/66,469-   Patent Document 16: International Patent Publication WO 0/90,1469-   Patent Document 17: U.S. Pat. No. 6,022,307-   Patent Document 18: International Patent Publication WO 03/024,962-   Patent Document 19: International Patent Publication WO 03/029,245-   Patent Document 20: International Patent Publication WO 03/040,096-   Patent Document 21: International Patent Publication WO 03/097,617-   Patent Document 22: International Patent Publication WO 03/099,821-   Patent Document 23: International Patent Publication WO 97/27,200-   Patent Document 24: U.S. Pat. No. 3,649,641-   Non-Patent Document 1: Bioorg. Med. Chem. Lett., 11 (2001), 1081-   Non-Patent Document 2: J. Med. Chem., 43 (2000), 683-   Non-Patent Document 3: Eur. J. Med. Chem., 36 (2001), 333-   Non-Patent Document 4: Russ. J. Org. Chem., 39 (2003), 893-   Non-Patent Document 5: Aknos Consulting and Solutions GmbH Co.,    Catalog: Akos samples-   Non-Patent Document 6: Phosphorus, sulfur and silicon and related    Elements, 157 (2000), 107-   Non-Patent Document 7: Zhurnal Organisheskoi Khimii., 9 (1973), 2416-   Non-Patent Document 8: Zhurnal Organisheskoi Khimii., 5 (1969), 1498-   Non-Patent Document 9: Phosphorus, sulfur and silicon and related    Elements, 157 (2000), 107-   Non-Patent Document 10: Chinese Chemical Letters, 10(3), (1999). 189-   Non-Patent Document 11: Indian Journal of Chemistry, Section B:    Organic Chemistry Including Medicinal Chemistry, 35B(7), (1996), 715

DISCLOSURE OF INVENTION The Problem to be Solved in the Invention

The purpose of the present invention is to provide novel compoundshaving PDE 7 inhibiting activity, and PDE 7 inhibitors containing saidinhibitors as an active ingredient. Further, the present inventionprovides useful intermediate compounds for manufacturing theabove-mentioned novel compounds.

The compounds of the present invention inhibit PDE 7 selectively, andtherefore, enhance cellular cAMP level. Consequently, the compounds ofthe present invention are useful for treating various kinds of diseasessuch as allergic diseases, inflammatory diseases or immunologicaldiseases by inhibiting the activation of T-cells.

For example, the compounds of the present invention are useful fortreating or preventing the diseases such as bronchial asthma, chronicbronchitis, chronic obstructive pulmonary disease, allergic rhinitis,psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoidarthritis, multiple sclerosis, systemic lupus erythematosus,inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis,sepsis, Crohn's disease, rejection reaction in transplantation, GVHdisease, restenosis after angioplasty.

Means to Solve the Problem

Through extensive investigations of researching compounds having thecapabilities of inhibiting PDE 7, the present inventors discovered thatthe compounds having thienopyrazole skeleton in the molecule representedby the formula (I) mentioned below possess potent and selective PDE 7inhibiting effect, and thus, completed the present invention.

Accordingly, as one aspect of the present invention, it is providedthienopyrazole compounds represented by the following formula (I):

wherein:

R¹ is substituted or unsubstituted C₃-C₈ alkyl group, substituted orunsubstituted cycloalkyl group or substituted or unsubstitutedheterocycloalkyl group;

R² is a hydrogen atom or substituted or unsubstituted C₁-C₃ alkyl group;

R³ is a hydrogen atom, substituted or unsubstituted C₁-C₃ alkyl group,or a halogen atom;

R⁴ is substituted or unsubstituted aryl group, substituted orunsubstituted heteroaryl group, or a group —CONR⁵R⁶ or —CO₂R⁷;

R⁵ and R⁶ are, same or different from each other, a hydrogen atom; C₁-C₆alkyl group which may be substituted by a halogen atom, substituted orunsubstituted aryl group, substituted or unsubstituted heteroaryl group,substituted or unsubstituted heterocycloalkyl group, substituted orunsubstituted cycloalkyl group, a group —NR⁷COR⁸, —COR⁸, —NR⁹R¹⁰;substituted or unsubstituted cycloalkyl group; substituted orunsubstituted heterocycloalkyl group; substituted or unsubstituted arylgroup; substituted or unsubstituted heteroaryl group; or substituted orunsubstituted heterocycloalkyl group in which the ring is formedtogether with the nitrogen atom binding R⁵ and R⁶;

R⁷ is a hydrogen atom, or substituted or unsubstituted C₁-C₃ alkylgroup;

R⁸ is substituted or unsubstituted heterocycloalkyl group, or a a group—OH, —OR⁷ or —NR⁹R¹⁰;

R⁹ and R¹⁰ are, same or different from each other, a hydrogen atom,substituted or unsubstituted C₁-C₃ alkyl group, substituted orunsubstituted heterocycloalkyl group; substituted or unsubstituted acylgroup; a group —SO₂R⁷, or substituted or unsubstituted heterocycloalkylgroup in which the ring is formed together with the nitrogen atombinding R⁵ and R⁶;

or pharmaceutically acceptable salts.

Another aspect of the present invention, it is provided PDE 7 inhibitingcomposition containing the thienopyrazole compounds mentioned above, orpharmaceutically acceptable salts as an active ingredient.

Still another aspect of the present invention, it is provided a methodfor preparing the thienopyrazole compounds represented by the formula(I).

In particular, the method is comprised by chlorination of pyrazole-5-onederivative represented by the formula (VI):

wherein, R¹ and R² have the same meanings as defined above; and then, byan electrophilic substitution reaction of the resulting compound withoutseparation to give the pyrazole derivative of the formula (IV):

wherein, R¹, R² and R³ have the same meanings as defined above; then, byreacting the resulting pyrazole derivative of formula (IV) with thecompound of the formula (III) in the presence of base:

wherein, R⁴ has the same meanings as defined above;

to give the compound of the formula (II):

wherein, R¹, R², R³ and R⁴ have the same meanings as defined above; andthen, by treating the resulting compound of formula (II) with base togive thienopyrazole compound of the formula (I):

wherein, R¹, R², R³ and R⁴ have the same meanings as defined above.

Additionally, the intermediate compound of the formula (IV) can beobtained by electrophilic substitution reaction of chloropyrazolecompound of the formula (V):

wherein, R¹ and R² have the same meanings as defined above.

Furthermore, the compound of the formula (I) can be obtained by one potsynthesis from the compound of the formula (IV) without separation ofthe intermediate compound of the formula (II). In particularly, it isprovided the manufacturing method for the compound of the formula (I),in which R³ is a hydrogen atom.

Effects of the Invention

The compounds of the present invention inhibit PDE 7 selectively, andtherefore, the compounds of the present invention are useful fortreating or preventing the diseases such as bronchial asthma, chronicbronchitis, chronic obstructive pulmonary disease, allergic rhinitis,psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoidarthritis, multiple sclerosis, systemic lupus erythematosus,inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis,septicemia sepsis, Crohn's disease, rejection reaction oftransplantation, GVH disease, restenosis after angioplasty.

Further, the compounds of the formula (II) and (IV) are importantintermediate compounds for synthesis of the present compound of formula(I), and therefore, by using these intermediates, the compounds of thepresent invention represented by the formula (I) can be obtained bysimple and easy way.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be explained more specifically asfollowing.

The term “C_(n)-C_(m) alkyl group” of the present invention includes astraight or a branched-chained alkyl group having n to m carbon atoms.The term “cycloalkyl group” means cycloalkyl group having 3 to 8 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like. The term “heterocycloalkyl group”may be 3 to 7 membered monocyclic or polycyclic heterocyclic groupcontaining the same or different 1 to 4 hetero atom(s) such as oxygen,nitrogen or sulfur atom(s), and examples may include piperidinyl,pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl,morpholinyl, azetidinyl, imidazolidinyl, oxazolidinyl,hexahydropyrrolidinyl, octahydroindolidinyl, octahydroquinolidinyl,octahydroindolyl, and oxo-derivatives thereof.

The “halogen atom” includes chlorine, fluorine, bromine and iodine. Theterm “aryl group” may be aromatic hydrocarbon group, which consists ofmono-benzene ring, or binding or condensed benzene ring, such as phenyl,naphthyl, biphenyl and the like; and dicyclic or tricyclic group, whichconsists of benzene ring condensed with cycloalkyl or heterocyclic ring,such as 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, indoline,coumarone and the like.

The term “heteroaryl group” may be 5 to 7 membered monocyclic heteroarylgroup or polycyclic heteroaryl group, and having 2 to 8 carbon atomswith 1 to 4 hetero atom(s) such as oxygen, nitrogen, sulfur atom(s), inwhich the polycyclic heteroaryl group has condensed ring system by thesame or different nomocyclic heteroaryl or benzene ring each other; orpolycyclic group which is consisted of heteroaryl group condensed withcycloalkyl or heterocycloalkyl ring.

The examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl,pyrazinyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, tetrazolyl,pyridinyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzothiophenyl,isoxazolyl, indazolyl, benzoimidazolyl, phthalazinyl, triazolyl,benzooxazolyl, benzothiazolyl, dihydrocyclopentapyridinyl,dihydropyrropyridinyl and the like.

Examples of suitable substituent of the present invention may includestraight, branched-chained or cyclic C₁-C₈ alkyl group, which may besubstituted by one or more methyl, ethyl, propyl, isopropyl, n-butyl,t-butyl, cyclohexyl, cycloheptyl, methoxymethyl, hydroxymethyl,trifluoromethyl, C₁-C₃ alkoxy group, halogen atom, and hydroxyl group;hydroxyl group; cyano group; substituted or unsubstituted alkoxy groupsuch as methoxy, ethoxy group; amino group which may be substituted byC₁-C₆ alkyl group or acyl group such as amino, methylamino, ethylamino,dimethylamino, acylamino and the like; carboxylic group; substituted orunsubstituted ester group; phosphate group; sulfonic group; substitutedor unsubstituted aryl group; substituted or unsubstituted heteroarylgroup; saturated or unsaturated heterocycloalkyl group which may besubstituted; substituted or unsubstituted carbamoyl group; substitutedor unsubstituted amide group; substituted or unsubstituted thioamidegroup; halogen atom; nitro group; substituted or unsubstituted sulfonegroup; substituted or unsubstituted sulfonylamide group; oxo group;substituted or unsubstituted urea group; straight, branched-chained orcyclic alkenyl group such as ethenyl, propenyl, cyclohexenyl and thelike.

Examples of suitable substituent of “C₃-C₈ alkyl group which may besubstituted” in the group of R¹ may include hydroxyl group, halogenatom, alkoxy group and the like, and examples of suitable substituent of“cycloalkyl group which may be substituted” in the group of R¹ includehydroxyl group, alkoxy group, oxo group, C₁-C₃ alkyl group such asmethyl group. Examples of suitable substituent of “heterocyclo alkylgroup which may be substituted” in the group of R¹ may include C₁-C₃alkyl group such as methyl group.

Examples of suitable substituent of “C₁-C₃ alkyl group which may besubstituted” in the group R² may include hydroxyl group, alkoxy group,halogen atom such as fluorine atom. Further, examples of suitablesubstituent of C₁-C₃ alkyl group which may be substituted” in the groupR³ include hydroxyl group, alkoxy group, halogen atom such as fluorineatom.

Examples of suitable substituent of “aryl group which may besubstituted” and “heteroaryl group which may be substituted” in thegroup R⁴ may include hydroxyl group, halogen atom, heterocycloalkylgroup which may be substituted by C₁-C₆ alkyl group.

Examples of suitable substituent of “cycloalkyl group which may besubstituted” in the groups R⁵ and R⁶ may include hydroxyl group; oxogroup; carboxyl group; carboxyl ester group; cyano group; C₁-C₆ alkylgroup {in which said C₁-C₆ alkyl group may be substituted by C₁-C₃alkoxyl group, hydroxyl group, amino group which may be substituted byC₁-C₆ alkyl group, arylsulfonyloxy group, heterocycloalkyl group (inwhich said heterocycloalkyl group may be substituted by hydroxyl group,C₁-C₆ alkyl group, oxo group or acetyl group)}; amide group (in whichsaid amide group may be substituted by cycloalkyl group or C₁-C₆ alkylgroup which may be substituted by hydroxyl group); heterocycloalkylamidegroup which may be substituted by C₁-C₆ alkyl group;heterocycloalkylamide group which may be substituted by hydroxyl group;amino group (in which said amino group may be substituted by C₁-C₆ alkylgroup which may be substituted by C₁-C₃ alkoxy group and acyl group);heterocycloalkyl group {in which said heterocycloalkyl group may besubstituted by C₁-C₆ alkyl group (in which said alkyl group may besubstituted by hydroxyl group), oxo group, acyl group, hydroxyl group,amino group which may be substituted by C₁-C₆ alkyl group, amino groupwhich may be substituted by acyl group, C₁-C₃ alkoxy group,alkoxycarbonyl group, carboxyl group, aminocarbonyl group which may besubstituted by C₁-C₆ alkyl group, or sulfonyl group which may besubstituted by C₁-C₆ alkyl group}.

Examples of suitable substituent of “heterocycloalkyl group which may besubstituted” may include benzyl group; acyl group; oxo group;heterocycloalkyl group (in which said heterocycloalkyl group may besubstituted by C₁-C₆ alkyl group, acyl group, sulfonyl group which maybe substituted by C₁-C₆ alkyl group or alkoxycarbonyl group); C₁-C₆alkyl group which may be substituted by carboxyl group or carboxylicester group; amido group which may be substituted by C₁-C₆ alkyl group;heterocycloalkylamide group which may be substituted by C₁-C₆ alkylgroup; sulfonyl group which may be substituted by C₁-C₆ alkyl group;sulfonamide group which may be substituted by C₁-C₆ alkyl group;cycloalkyl group which may be substituted by oxo or hydroxyl group;alkoxycarbonyl group, and the like.

Further, examples of suitable substituent of “aryl group which may besubstituted” in the group of R⁵ and R⁶ may include halogen atom; nitrogroup; cyano group; acyl group; amino group which may be substituted byacyl group; amide group (in which said amide group may be substituted byC₁-C₆ alkyl group which may be substituted by C₁-C₃ alkoxy group orC₁-C₆ alkyl group which may be substitute by hydroxyl group);alkoxycarbonylamino group; alkoxycarbonyl group; alkoxy group (in whichsaid alkoxy group may be substituted by carboxyl group, carboxylic estergroup, or amide group); carbonyl group; carboxyl group; carboxylic estergroup; carbamoyl group; sulfonic group; sulfonamide group; aminosulfonylgroup; C₁-C₆ alkyl group (in which said alkyl group may be substitutedby C₁-C₃ alkoxy group, hydroxyl group or heterocycloalkyl group whichmay be substituted by C₁-C₆ alkyl group); heterocycloalkylamide groupwhich may be substituted by C₁-C₆ alkyl group; heterocycloalkyl groupwhich may be substituted by hydroxyl group; acetic acid group; aceticacid amide group; or heterocycloalkyl group (in which saidheterocycloalkyl group may be substituted by hydroxyl group, oxo group,acyl group, C₁-C₆ alkyl group, amino group which may be substituted byC₁-C₆ alkyl group, amino group which may be substituted by acyl group,C₁-C₃ alkoxy group, alkoxycarbonyl group, and the like).

Examples of suitable substituent of “heteroaryl group which may besubstituted” in the group of R⁵ and R⁶ may include halogen atom; acylgroup; amide group {in which said amide group may be substituted byC₁-C₆ alkyl group (in which said alkyl group may be further substitutedby amino group which may be substituted by C₁-C₆ alkyl group or hydroxylgroup)}; cycloalkyl group which may be substituted by hydroxyl group;cycloheteroalkyl group which may be substituted by C₁-C₆ alkyl group oracyl group; heterocycloalkylamide group which may be substituted byC₁-C₆ alkyl group; heterocycloalkylamide group which may be substitutedby hydroxyl group; oxo group; acylamino group; C₁-C₆ alkyl group (inwhich said alkyl group may be substituted by cycloheteroalkyl groupwhich may be substituted by hydroxyl group, acyl group orcycloheteroalkyl group which may be substituted hydroxyl group);carboxyl group; carboxylic ester group; sulfonyl group; heterocycloalkylgroup (in which said heterocycloalkyl group may be substituted byhydroxyl group, oxo group, acyl group, C₁-C₆ alkyl group, amino groupwhich may be substituted by C₁-C₆ alkyl group, amino group which may besubstituted by acyl group, C₁-C₃ alkoxy group, alkoxycarbonyl group, andthe like).

Examples of suitable substituent of “substituted or unsubstitutedheterocycloalkyl group which is formed said ring system together withnitrogen atom which they are bonded” may include acyl group; amidegroup; C₁-C₆ alkyl group or C₁-C₃ alkoxy group; carbonyl group; carboxylgroup; carboxylic ester group; hydroxyl group; carbamoyl group;sulfonamide group; aminosulfonic group; oxo group; and the like.

Examples of suitable substituent of “C₁-C₃ alkyl group which may besubstituted” in the group R⁷ may include hydroxyl group, alkoxy group,halogen atom such as fluorine atom, and the like.

Examples of suitable substituent of “heterocycloalkyl group which may besubstituted” in the group R⁸ may include hydroxyl group, alkoxy group,oxo group, acyl group, C₁-C₆ alkyl group, C₁-C₃ alkoxy group, carboxylgroup, amide group, and the like.

In the groups R⁹ and R¹⁰, examples of suitable substituent of “C₁-C₃alkyl group which may be substituted” may include hydroxyl group, alkoxygroup and the like. Further, examples of suitable substituent of“heterocycloalkyl group which may be substituted” may include C₁-C₆alkyl group, hydroxyl group, alkoxy group, oxo group, acyl group and thelike, and examples of suitable substituent of “acyl group which may besubstituted” may include C₁-C₆ alkyl group, hydroxyl group, alkoxy groupand the like.

Examples of suitable substituent of “substituted or unsubstitutedheterocycloalkyl group which is formed said ring system together withnitrogen atom which they are bonded” include acyl group, amide group,C₁-C₆ alkyl group, C₁-C₃ alkoxy group, carbonyl group, carboxyl group,carboxylic ester group, hydroxyl group, carbamoyl group, sulfonamidegroup, aminosulfonic group, and the like.

Preferable compounds of the formula (I) of the present invention mayinclude the compounds wherein R¹ is cyclohexyl group, cycloheptyl groupor tetrahydropyranyl group; R² is methyl group; R³ is a hydrogen atom;and R⁴ is the group —NR⁵R⁶ (in which one of these R⁵ and R⁶ is ahydrogen atom).

It is understood that when the compounds of the formula (I) of thepresent invention exist in the tautomeric mixtures, each tautomericisomers per se, as well as the mixture thereof. Furthermore, theradiolabelled compound of the formula (I) shall be included within thescope of the compounds of the present invention.

The compounds of the present invention may contain one or moreasymmetric carbon atom and therefore, the compounds of the presentinvention may exist as optically isomer of (R)-form or (S)-form, racemicforms, as well as diastereomers. Further, the compounds of the presentinvention may exist as geometrical isomer such as (Z)-form or (E)-formdue to the double bond in the substituent. Therefore, the compounds ofthe present invention should include these isomers per se as well as theisomeric mixtures thereof.

The compounds of the present invention may form acid additional saltthereof with various acids. Examples of the acid additional salt includethe salts with inorganic acid such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; salts with organic acid such as formic acid, acetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, citric acid, tartaric acid,benzoic acid, picric acid, methanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, trichloroacetic acid, trifluoroacetic acid,asparaginic acid, glutamic acid and the like.

The compounds of the present invention may form pharmaceuticallyacceptable salts by treating with various kinds of metal, especiallyalkali metal or alkali earth metal. These salts may include sodium salt,potassium salt, calcium salt and the like.

The following compounds are preferable thienopyrazole compounds of theformula (I) of the present invention.

-   Ethyl 1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate;-   N-Benzyl-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{4-[Acetyl(methyl)amino]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[4-(Acetylamino)-3-methoxyphenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}phenylcarbamate;-   tert-Butyl    5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-indolinecarboxylate;-   1-Cyclohexyl-N-(2,3-dihydro-1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(4-morpholinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(3-nitrophenyl)-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   N-(3-Aminophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   N-[3-(Acetylamino)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[(methylamino)carbonyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(1-propionyl-2,3-dihydro-1H-indol-5-yl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-indolinecarboxylate;-   1-Cyclohexyl-N-(1-isobutyryl-2,3-dihydro-1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(1-Butyryl-2,3-dihydro-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[1-(2,2-dimethylpropanoyl)-2,3-dihydro-1H-indol-5-yl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[4-(Acetylamino)-3-chlorophenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(ethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-4-[4-(methoxymethyl)phenyl]-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(hydroxymethyl)phenyl]-3-methyl-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylcarbonyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[(methylsulfonyl)amino]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[(methylamino)sulfonyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-2,3-dihydro-1H-indol-5-yl}acetamide;-   1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(4-({[(2-methoxyethyl)amino]carbonyl}phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(4-Acetylphenyl)-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}benzoate;-   4-{[(1-Cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]-amino}benzoic    acid;-   1-Cyclohexyl-N-(2-methoxy-4-nitrophenyl)-3-methyl-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   N-(4-Amino-2-methoxyphenyl)-1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   N-[4-(Acetylamino)-2-methoxyphenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(isopropylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[6-(Acetylamino)-3-pyridinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(4-methoxyphenyl)-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N,1-Dicyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{4-[(tert-butylamino)carbonyl]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{5-([(isopropylamino)carbonyl]-2-pyridinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(formylamino)phenyl]-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   tert-Butyl    4-[(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}phenyl)sulfonyl]-1-piperazinecarboxylate;-   1-Cyclohexyl-3-methyl-N-[4-(1-piperazinylsulfonyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylsulfonyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(methylsulfonyl)phenyl]-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indol-5-yl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(1-Acetyl-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-cyclopropyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(1-Benzyl-4-piperidinyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(1-Acetyl-4-piperidinyl)-1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   Ethyl    (4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}phenoxy)acetate;-   (4-{(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl)amino}phenoxy)acetic    acid;-   1-Cyclohexyl-3-methyl-N-{4-[(2-(methylamino)-2-oxoethoxy]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    (4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}phenyl)acetate;-   (4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}phenyl)acetic    acid;-   1-Cyclohexyl-3-methyl-N-{4-[2-(methylamino)-2-oxoethyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    4-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}phenyl)-1-piperazinecarboxylate;-   1-Cyclohexyl-3-methyl-N-[4-(1-piperazinyl)phenyl]-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   N-[4-(4-Acetyl-1-piperazinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(trans-4-hydroxycyclohexyl)-3-methyl-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(4-oxocyclohexyl)-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[(2-(4-methyl-1-piperazinyl)-2-oxoethoxy]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[2-(dimethylamino)-2-oxoethoxy]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   2-{4-[4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}phenyl]sulfonyl}-1-piperazinyl)ethyl    acetate;-   1-Cyclohexyl-N-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]sulfonyl}-phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[trans-4-(Acetylamino)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl 1-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate;-   N-[4-(Acetylamino)phenyl]-1-cyclopentyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   Ethyl 1-cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate;-   N-[4-(Acetylamino)phenyl]-1-cycloheptyl-3-methyl-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N,3-dimethyl-N-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(4-pyridinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(3-pyridinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(4-nitrophenyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(4-Aminophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[4-(Acetylamino)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(methoxyacetyl)amino]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-2-pyridinecarboxylate;-   5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-pyridinecarboxylic    acid;-   1-Cyclohexyl-3-methyl-N-{6-[(methylamino)carbonyl]-3-pyridinyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{6-[(dimethylamino)carbonyl]-3-pyridinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide    methanesulfonate;-   N-(4-Cyanophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{3-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{3-[(methylamino)sulfonyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cycloheptyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[3-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[(4-(Acetylamino)-3-methoxyphenyl]-1-cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(3,5-dichloro-4-pyridinyl)-3-methyl-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   5-(4-Bromophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole;-   1-Cyclohexyl-3-methyl-5-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole;-   1-Cyclohexyl-3-methyl-5-[4-(4-methyl-1,4-diazepam-1-yl)phenyl]-1H-thieno[2,3-c]pyrazole;-   1-Cyclohexyl-N-{3-fluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{3-fluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide    HCl salt;-   Ethyl    cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexanecarboxylate;-   cis-4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclohexanecarboxylic    acid;-   1-Cyclohexyl-N-[cis-4-(hydroxymethyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    trans-4-({[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino)methyl}cyclohexanecarboxylate;-   1-Cyclohexyl-N-{[trans-4-(hydroxymethyl)cyclohexyl]methyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    trans-4-({[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexylcarbamate;-   N-(trans-4-Aminocyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-(1-tetrahydro-2H-pyran-4-yl-4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[1-(1,4-diazaspiro[4.5]decan-8-yl)-4-piperidinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[1-(4-oxocyclohexyl)-4-piperidinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[1-(trans-4-hydroxycyclohexyl)-4-piperidinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    4-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}phenyl)-1-piperidinecarboxylate;-   1-Cyclohexyl-3-methyl-N-[4-(4-piperidinyl)phenyl]-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[(4-(1-methyl-4-piperidinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(4-ethyl-1-piperazinyl)-3-fluorophenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1,4-diazepam-1-yl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-2-methoxybenzoate;-   4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-methoxybenzoic    acid;-   1-Cyclohexyl-N-{3-methoxy-4-[(4-methyl-1-piperazinyl)carbonyl]-phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(3-methoxy-4-(4-morpholinylcarbonyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)carbonyl]-3-methoxyphenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)amino]carbonyl}-3-methoxyphenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(3-methoxy-4-{[(2-methoxyethyl)amino]carbonyl}-phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{3-methoxy-4-[(methylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]-3-methoxyphenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[3-Chloro-4-(4-methyl-1-piperazinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)-3-fluorophenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[3-fluoro-4-(4-oxo-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-cyclohexyl-N-[3-fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[3-Chloro-4-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[3-Chloro-4-(4-oxo-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[3-Chloro-4-(4-hydroxy-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{3-fluoro-4-[4-(methylamino)-1-piperidinyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    1-(2-chloro-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}phenyl)-4-piperidinyl(methyl)carbamate;-   N-{3-Chloro-4-[4-(methylamino)-1-piperidinyl]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-1-piperazinyl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{trans-4-(4-methyl-1,4-diazepam-1-yl)-cyclohexyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[trans-4-(4-methoxy-1-piperidinyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Benzyl    4-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1,4-diazepam-1-carboxylate;-   1-Cyclohexyl-N-[trans-4-(1,4-diazepam-1-yl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[trans-4-(4-Acetyl-1,4-diazepam-1-yl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{trans-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{cis-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[trans-4-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)-cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[trans-4-(4-oxo-1-piperidinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[trans-4-(4-hydroxy-1-piperidinyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{trans-4-[(2R,6S)-2,6-dimethylmorpholinyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{cis-4-[(2R,6S)-2,6-dimethylmorpholinyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{trans-4-[4-(methylamino)-1-piperidinyl]-cyclohexyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(trans-4-{4-[Acetyl(methyl)amino]-1-piperidinyl}cyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{trans-4-[4-(dimethylamino)-1-piperidinyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    1-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinylcarbamate;-   tert-Butyl    1-(cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinylcarbamate;-   N-[trans-4-(4-Amino-1-piperidinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[cis-4-(4-Amino-1-piperidinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    4-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate;-   tert-Butyl    4-(cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate;-   1-Cyclohexyl-3-methyl-N-[trans-4-(l-piperazinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-cyclohexyl-3-methyl-N-[cis-4-(1-piperazinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[trans-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1,4-diazapam-1-yl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic    acid;-   3-Methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[3-Fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylmethyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[2-(dimethylamino)ethyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[2-(4-morpholinyl)ethyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[(3-methyl-2,5-dioxo-1-imidazolidinyl)-methyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)-phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexanecarboxylate;-   4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-yl)carbonyl]-amino}cyclohexanecarboxylic    acid;-   1-Cyclohexyl-N-[4-(hydroxymethyl)cyclohexyl]-3-methyl-1-thieno-[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]-cyclohexyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(4-Cyanocyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}ethyl(methyl)carbamate;-   1-Cyclohexyl-3-methyl-N-[2-(methylamino)ethyl]-1H-thieno-[2,3-c]pyrazole-5-carboxamide;-   N-{2-[Acetyl(methyl)amino]ethyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{2-[methyl(methylsulfonyl)amino]ethyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    (4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-piperidinyl)acetate;-   (4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-1-piperidinyl)acetic    acid;-   Ethyl    2-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-piperidinyl)-2-methylpropanoate;-   2-(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-piperidinyl)-2-methylpropanoic    acid;-   1-Cyclohexyl-N-[2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)-ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{2-[methyl(4-morpholinylcarbonyl)amino]-ethyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{2-[[(dimethylamino)carbonyl](methyl)amino]ethyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}ethyl(methyl)carbamate;-   1-Cyclohexyl-N-{2-[(methoxyacetyl)(methyl)amino]ethyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{2-[glycoloyl(methyl)amino]ethyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)(methyl)amino]carbonyl}cyclohexyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    (1S,3S)-3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclopentanecarboxylate;-   (1S,3S)-3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclopentanecarboxylic    acid;-   1-Cyclohexyl-3-methyl-N-[2-(4-methyl-2,3-dioxo-1-piperazinyl)-ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{(1S,3S)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    (1R,3R)-3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclopentanecarboxylate;-   (1R,3R)-3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclopentanecarboxylic    acid;-   1-Cyclohexyl-N-{(1R,3R)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{1-[(dimethylamino)carbonyl]-4-piperidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylcarbonyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{4-[(methylamino)carbonyl]cyclohexyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(cyclopropylamino)carbonyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)carbonyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{1-[(dimethylamino)sulfonyl]-4-piperidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}-1-piperidinecarboxylate;-   1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[(3S)-1-Benzylpyrrolidinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[(3S)-pyrrolidinyl]-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{(3S)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(2,5-dioxo-1-imidazolidinyl)methyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    1-[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-4-piperidinecarboxylate;-   1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-4-piperidinecarboxylic    acid;-   1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-N-methyl-4-piperidinecarboxamide;-   Ethyl    (3S)-1-[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-3-piperidinecarboxylate;-   N-[(6S,7aS)-1,3-Dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[(6S,7aS)-2-Methyl-1,3-dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   {1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-3-piperidinyl}methanol;-   N-{4-[(Dimethylamino)carbonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[6-(2-oxo-1-imidazolidinyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(1S,3S)-3-(hydroxymethyl)cyclopentyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{(1S,3S)-3-[(2,5-dioxo-1-imidazolidinyl)methyl]-cyclopentyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(2,5-dioxo-1-imidazolidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[(4-(3-methyl-2,5-dioxo-1-imidazolidinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[6-(2-oxo-1-imidazolidinyl)-3-pyridinyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[(2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(3R)-3-hydroxypyrrolidinyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{3-fluoro-4-[(3R)-3-hydroxypyrrolidinyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{3-[(4-hydroxy-1-piperidinyl)sulfonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{4-[4-{[tert-Butyl(dimethyl)silyl]oxy}-1-piperidinyl]sulfonyl}-phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)sulfonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(2-hydroxyethyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[3-Fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(2-oxo-1-imidazolidinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   4-[(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclohexyl)amino]-4-oxobutanoic    acid;-   1-Cyclohexyl-N-[4-(2,5-dioxo-1-pyrrolidinyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(1,1-dioxide-2-isothiazolidinyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Benzyl    [{[(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclohexyl)amino]carbonyl}(methyl)amino]acetate;-   1-cyclohexyl-3-methyl-N-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2,5-dioxo-1-imidazolidinyl)-ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[3-(3-methyl-2,5-dioxo-1-imidazolidinyl)-propyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-({[(2-hydroxyethyl)(methyl)amino]carbonyl}amino)-cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(3-methyl-2-oxo-1-imidazolidinyl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}propanoate;-   N-[(1-Cyclohexyl)-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-β-alanine;-   tert-Butyl    {[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}acetate;-   {[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}acetic    acid;-   1-Cyclohexyl-3-methyl-N-[3-(4-morpholinyl)-3-oxopropyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}ethylcarbamate;-   N-(2-Aminoethyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[3-(dimethylamino)-3-oxopropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{3-[methyl(1-methyl-4-piperidinyl)amino]-3-oxopropyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[3-(4-hydroxy-1-piperidinyl)-3-oxopropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(4-morpholinyl)-2-oxoethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-cyclohexyl-N-[2-(dimethylamino)-2-oxoethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[2-(4-hydroxy-1-piperidinyl)-2-oxoethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[3-(4-methyl-1-piperazinyl)-3-oxopropyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{2-[methyl(1-methyl-4-piperidinyl)amino]-2-oxoethyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[2-(1,1-dioxide-2-isothiazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(2-({[(2-hydroxyethyl)(methyl)amino]carbonyl}amino)-ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2-oxo-1-imidazolidinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}butanoate;-   4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-1-yl)carbonyl]-amino}butanoic    acid;-   1-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(dimethylamino)-4-oxobutyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[2-(2,4-dioxo-1,3-thiazolidin-3-yl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[1-(hydroxymethyl)cyclopropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{1-[(3-methyl-2,5-dioxo-1-imidazolidinyl)-methyl]cyclopropyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    [(2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}ethyl)amino]acetate;-   Methyl    [(aminocarbonyl)(2-{[(1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}ethyl)amino]acetate;-   1-Cyclohexyl-N-[2-(2,4-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(5-methyl-1,1-dioxide-1,2,5-thiadiazolidin-2-yl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   l-Cyclohexyl-N-[2-(3-ethyl-2,4-dioxo-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2,4-dioxo-1-imidazolidinyl)-ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(1S)-2-hydroxy-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(1S)-2-(2,5-dioxo-1-imidazolidinyl)-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[(3R)-1-Benzylpyrrolidinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[(3R)-pyrrolidinyl]-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{(3R)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(1R)-2-hydroxy-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(1R)-2-(2,5-dioxo-1-imidazolidinyl)-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(2S)-2-hydroxypropyl]-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(2R)-2-(2,5-dioxo-1-imidazolidinyl)propyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(2R)-2-hydroxypropyl]-3-methyl-3H-thieno[2,3-c]-pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(2S)-2-(2,5-dioxo-1-imidazolidinyl)propyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(1R)-1-(hydroxymethyl)propyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{(1R)-1-[(2,5-dioxo-1-imidazolidinyl)methyl]propyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{(1R)-1-[(2,5-dioxo-1-imidazolidinyl)methyl]-2-methylpropyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-2-methylpropylcarbamate;-   N-(2-Amino-1,1-dimethylethyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)-1,1-dimethylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(3-Amino-2,2-dimethylpropyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[3-(2,5-dioxo-1-imidazolidinyl)-2,2-dimethylpropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   (±)-1-Cyclohexyl-N-[trans-2-(hydroxymethyl)cyclopropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[4-(4-Hydroxy-1-piperidinyl)phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[4-(3-oxo-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[4-(3-oxo-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}benzoate;-   3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}benzoic    acid;-   1-Cyclohexyl-N-{3-[(dimethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[3-(4-morpholinylcarbonyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexanecarboxylate;-   trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)    carbonyl]amino}cyclohexanecarboxylic acid;-   N-{trans-4-[(Dimethylamino)carbonyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[trans-4-(4-morpholinylcarbonyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{trans-4-[(4-Hydroxy-1-piperidinyl)carbonyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-{trans-4-[(4-methyl-1-piperazinyl)carbonyl]cyclohexyl}-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[3-(4-morpholinyl)propyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(4-morpholinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[2-(1-piperidinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[trans-4-(Hydroxymethyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   (trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)methyl    p-toluenesulfonate;-   3-Methyl-N-[trans-4-(4-morpholinylmethyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{trans-4-[(Dimethylamino)methyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{trans-4-[(4-Acetyl-1-piperazinyl)ethyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{3-[(Dimethylamino)sulfonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[3-(methylsulfonyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{3-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[3-[(2-Hydroxyethyl)sulfonyl]phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[6-(4-hydroxy-1-piperidinyl)-3-pyridinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[2,3-difluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)-3-methylphenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[3-cyano-4-(4-hydroxy-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-2-(4-hydroxy-1-piperidinyl)benzoate;-   5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-(4-hydroxy-1-piperidinyl)benzoic    acid;-   N-[6-(4-Hydroxy-1-piperidinyl)-3-pyridinyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-1-tetrahydro-2H-pyran-4-yl-(1-tetrahydro-2H-pyran-4-yl-4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{6-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyridinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-(6-{[(2-hydroxyethyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{6-[(4-methyl-1-piperazinyl)carbonyl]-3-pyridinyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[6-({[2-(dimethylamino)ethyl]amino}carbonyl)-3-pyridinyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[6-{[(trans-4-hydroxycyclohexyl)amino]carbonyl}-3-pyridinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-{6-[(4-methyl-1,4-diazepam-1-yl)carbonyl]-3-pyridinyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}-1-piperidinecarboxylate;-   3-Methyl-N-(4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1-thieno-[2,3-c]pyrazole-5-carboxamide;-   N-{1-[(Dimethylamino)carbonyl]-4-piperidinyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    4-{4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}piperidin-1-yl}-1-piperidinecarboxylate;-   3-Methyl-N-(piperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-(1-acetylpiperidin-4-yl-4-piper    idinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-(1-methanesulfonylpiperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   tert-Butyl    4-(trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate;-   tert-Butyl    4-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate;-   3-Methyl-N-[trans-4-(1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[cis-4-(1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[trans-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-{trans-4-[4-(methylsulfonyl)-1-piperazinyl]cyclohexyl}-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[cis-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[1-(4-morpholinylcarbonyl)-4-piperidinyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-{1-[(4-methyl-1-piperazinyl)carbonyl]-4-piperidinyl}-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(trans-4-Hydroxycyclohexyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-(4-oxocyclohexyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[trans-4-(cis-2,6-Dimethylmorpholinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[cis-4-(cis-2,6-Dimethylmorpholinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-[6-(hydroxymethyl)-3-pyridinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Methyl    5-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}-2-pyridinecarboxylate;-   5-{[(3-Methyl-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}-2-pyridinecarboxylic    acid;-   N-(6-{[(trans-4-Hydroxycyclohexyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[6-({[2-(Dimethylamino)    ethyl]amino}carbonyl)-3-pyridinyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-(6-{[(1-methyl-4-piperidinyl)amino]carbonyl}-3-pyridinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(6-{[(1-Acetyl-4-piperidinyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[6-(4-morpholinylmethyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-N-{6-[(4-hydroxy-1-piperidinyl)methyl]-3-pyridinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{6-[(4-Acetyl-1-piperazinyl)methyl]-3-pyridinyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[trans-4-(4-methyl-2-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-2-oxo-1-piperazinyl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[trans-4-(3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[cis-4-(3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[trans-4-(4-methyl-3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[cis-4-(4-methyl-3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    1-(trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylate;-   Ethyl    1-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylate;-   N-{trans-4-[4-(Hydroxymethyl)-1-piperidinyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{cis-4-[4-(Hydroxymethyl)-1-piperidinyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[trans-4-(4-Hydroxy-J-piperidinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-(cis-4-{4-[(Dimethylamino)carbonyl]-1-piperidinyl}cyclohexyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   1-(trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylic    acid;-   N-(trans-4-{4-[(Dimethylamino)carbonyl]-1-piperidinyl}cyclohexyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   Ethyl    3-methyl-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxylate;-   3-Methyl-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic    acid;-   3-Methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[trans-4-(4-Ethyl-3-oxo-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-[cis-4-(4-Ethyl-3-oxo-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   N-{trans-4-[(4-Ethyl-3-oxo-1-piperazinyl)methyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-{trans-4-[(4-methyl-3-oxo-1-piperazinyl)methyl]-cyclohexyl}-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;-   3-Methyl-N-[4-(4-methyl-2-oxo-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;

The compounds represented by the formula (I) of the present inventionmay be prepared by the following methods.

(wherein, R¹, R², R³ and R⁴ have same meanings mentioned above; L isC₁-C₃ lower alkyl group)

First, the compound (VI) obtained from the compound (VIII) by reactingwith R¹NHNH₂ (VII) in accordance with the known method (e.g.,International Patent Publication WO 03/053,975). Namely, the compound(VIII) is reacted with 1 to 2 equivalents, preferably about 1 equivalentof the compound (VII) in the solvent or absent of the solvent at roomtemperature to 120° C. The solvent to be used in the reaction isinorganic acid aqueous solution such as hydrochloric acid or sulfuricacid; aromatic carbon hydrate such as benzene or toluene; organic acidsuch as acetic acid; ethers such as 1,4-dioxane or tetrahydrofuran;halogenated hydrocarbons such as dichloromethane; alcohols such asmethanol or ethanol; or the mixture solvent there of.

After the reaction is completed, the reaction mixture is neutralized andthe mixture is extracted with an organic solvent, which is nonmisciblesolvent with water, and the organic layer is washed sequentially withwater and saturated saline solution. Then, the compound (VI) can beobtained by removal of the solvent. This compound (VI) can be purifiedby recrystallization, if necessary.

The starting compounds (VII) and (VIII) to be used in this reaction canbe commercially available or can be known compounds (e.g., J. Org.Chem., 1981, 46, 5414-5415). Further, the compounds (VII) can be used assalt with acidic compounds, such as hydrochloric acid salt or aceticacid salt.

Then, the resulting compound (VI) is converted to the compound (V) inaccordance with the common method. Namely, the reaction can be conductedby reacting the compound (VI) with 1 to 6 equivalents of halogenatingreagent such as phosphorous oxychloride or thionyl chloride in aromatichydrocarbon solvent such as benzene or toluene, or the absence of thesolvent, at room temperature to refluxing temperature of the solvent for1 to 12 hours. After the reaction is completed, the compound (V) can beobtained by removal of the solvent.

The obtained compound (V) is converted, without further purification, tothe compound (IV) by an electrophilic substitution reaction. Forexample, the compound, (V) in which R³ is a hydrogen atom, can beobtained by Vilsmeier reaction with the reaction reagent prepared from 1to 5 equivalents of phosphorus oxychloride, in the amide solvent such asN,N-dimethylformamide. The reaction is carried out at room temperatureto 120° C. for 1 to 12 hours.

After the reaction is completed, inorganic base aqueous solution such assodium hydroxide aqueous solution is added to the reaction mixture andthe mixture is extracted with an organic solvent, which is nonmisciblesolvent with water, and the organic layer is washed sequentially withwater and saturated saline solution. Then, the compound (IV) can beobtained by removal of the solvent. This compound (IV) can be purifiedby column chromatography or recrystallization, if necessary.

Further, the compound (IV) can be converted directly from the compound(IV) by Vilsmeier reaction in single process, or one-pot synthesisreaction without separation of the intermediate compound (V). Namely,the compound (VI) is treated with 2 to 5 equivalents of phosphorousoxychloride without using the reaction solvent at room temperature to120° C. to obtain the compound (V) in the reaction mixture. Then, tothis reaction mixture containing the resulting compound (V) is addedformamide solvents such as N,N-dimethylformamide at 0° C. to 120° C.,and the Vilsmeier reaction is carried out at room temperature to 120° C.for 1 to 24 hours.

After the reaction is completed, inorganic base aqueous solution such assodium hydroxide aqueous solution is added to the reaction mixture andthe mixture is extracted with an organic solvent, which is nonmisciblesolvent with water, and the organic layer is washed sequentially withwater and saturated saline solution. Then, the compound (IV) can beobtained by removal of the solvent. This compound (IV) can be purifiedby column chromatography or recrystallization, if necessary.

Then, the obtained compound (IV) is converted to the compound (II). Thereaction is carried out by treating the compound (IV) with 1 to 1.5equivalents of the compound (III), in the solvent at room temperature to80° C. for 0.5 to 8 hours. The solvent to be used in this reaction ispolar solvent such as acetonitrile or N,N-dimethylformamide; ethers suchas 1,4-dioxane or tetrahydrofuran; halogenated hydrocarbons such asdichloromethane; alcohols such as methanol or ethanol; or the mixturesolvent thereof. In this reaction, the compound (III) is previouslytreated with base such as potassium carbonate, sodium hydride, potassiumtert-butoxide, sodium methylate or sodium hydroxide.

After the reaction is completed, water is added to the reaction mixtureand the mixture is extracted with an organic solvent, which isnonmiscible solvent with water, and the organic layer is washedsequentially with water and saturated saline solution. Then, thecompound (II) can be obtained by removal of the solvent. This compound(I) can be purified by column chromatography or recrystallization, ifnecessary.

Then, the obtained compound (II) is converted to the compound (I) of thepresent invention by ring formation reaction.

The reaction condition of this ring formation may vary depending on thevariety of the group R⁴. When the group R⁴ is the group: —CO₂R⁷, thecompound (I) can be obtained from the compound (II) by treating with 1to 1.5 equivalents of the base such as potassium carbonate, sodiumhydride, sodium methylate or sodium hydroxide in the solvent at 0° C. to80° C. for 0.5 to 24 hours. The solvent to be used in this reaction ispolar solvent such as acetonitrile or N,N-dimethylformamide; ethers suchas 1,4-dioxane or tetrahydrofuran; halogenated hydrocarbons such asdichloromethane; alcohols such as methanol or ethanol; or the mixturesolvent there of.

After the reaction is completed, water is added to the reaction mixtureand the mixture is extracted with an organic solvent, which isnonmiscible solvent with water, and the organic layer is washedsequentially with water and saturated saline solution. Then, thecompound (I) can be obtained by removal of the solvent. This compound(I) can be purified by column chromatography, if necessary.

Further, when the group R⁴ is the group: —CO₂R⁷, the compound (I) can beobtained from the compound (IV), without the separation of the compound(II) in the corresponding stepwise reaction.

When the group R⁴ is an aryl group which may be substituted or aheteroaryl group which may be substituted, the compound (I) can beobtained from the compound (II) by treating with 1 to 3 equivalents ofthe strong base such as lithium diisopropylamide or lithiumbis(trimethylsilyl)amide in the ethers such as diethylether ortetrahydrofuran.

After the reaction is completed, water is added to the reaction mixtureand the mixture is extracted with an organic solvent, which isnonmiscible solvent with water, and the organic layer is washedsequentially with water and saturated saline solution, then, the organicsolvent is removed off. The resulting residue is dissolved in alcoholssuch as methanol or ethanol, and the acid such as hydrochloric acid isadded to the mixture, and then, the mixture is stirred at roomtemperature to 60° C. to obtain the compound (I).

After the reaction is completed, water is added to the reaction mixtureand the mixture is extracted with an organic solvent, which isnonmiscible solvent with water, and the organic layer is washedsequentially with water and saturated saline solution. Then, thecompound (I) can be obtained by removal of the solvent. This compound(I) can be purified by column chromatography or recrystallization, ifnecessary.

In the case of the group R⁴ is the group: —CONR⁵R⁶, first, the compound(I) in which the group R⁴ is —CO₂R⁷ obtained by the method describedabove, is converted to the compound (I) in which the group R⁴ is —CO₂H.This conversion reaction is the hydrolysis reaction of ester compound,and can be carried out in the several manners. For example, thehydrolysis reaction can be carried out in the presence of the base suchas sodium hydroxide, in the solvent at room temperature to refluxingtemperature of the solvent. The solvent to be used in the reaction maybe alcohols such as methanol or ethanol; water; or the mixture solventthereof. After the reaction is completed, the reaction mixture iscondensed, and the mixture is neutralized by adding hydrochloric acid toobtain the compound (I) in which the group R⁴ is —CO₂H.

Then, the resulting compound (I) in which the group R⁴ is —CO₂H isconverted to the compound in which the group R⁴ is —CONR⁵R⁶ by amidationreaction in accordance with the several known methods. For example, thecompound (I) in which the group R⁴ is —CO₂H is converted to thecorresponding acid chloride by treating with the halogenating reagentsuch as phosphorous oxychloride or thionyl chloride. Then, the obtainedacid chloride is treated with the amine compound HNR⁵R⁶ in the presenceof base catalyst such as triethylamine in solvent at 0° C. to roomtemperature. The solvent to be used in the reaction may be halogenatedhydrocarbons such as dichloromethane; aromatic hydrocarbons such astoluene or benzene; ethers such as diethylether or tetrahydrofurane; orthe mixture solvent thereof.

After the reaction is completed, the reaction mixture is diluted withthe organic solvent, which is nonmiscible solvent with water, and theorganic layer is washed sequentially with water and saturated salinesolution. Then, the compound (I) in which the group R⁴ is —CONR⁵R⁶ canbe obtained by removal of the solvent. This compound can be purified bycolumn chromatography or recrystallization, if necessary.

All reaction mentioned above are well known, and the reagents to be usedor the reaction conditions to be applied can be easily established inaccordance with the standard text book and the examples mentioned later.Further, the other methods or modified methods for obtaining thecompound (I) of the present invention can be easily selected by theperson skilled in this field.

EXAMPLES

The present invention is illustrated in more detail by way of thefollowing Biological Test, Examples, and Manufacturing Examples.

The synthesis of the compounds of the present invention and intermediatecompounds to be used in the synthesis are illustrated in the Examplesand Manufacturing Examples mentioned later. Further, the physicochemicaldata and chemical structure of the compounds and intermediate compoundsobtained by the Examples and Manufacturing Examples are summarized inthe Tables mentions later.

The compound numbers in the Examples are identical to those in theTables.

It is to be noted that the present invention is not limited by thoseExamples in any way.

Biological Test 1:

Methods for Evaluating the PDE 7 Inhibiting Effect

The PDE 7 (phosphodiesterase VII) inhibiting effect of the compounds ofthe present invention was performed by the following method, which wasmodified assay method described in Biochemical. Pharmacol. 48(6),1219-1223 (1994).

-   (1) The active fraction of PDE 7 (phosphodiesterase VII) was    obtained. That is, MOLT-4 (obtainable from ATCC as ATCC No.    CRL-1582), which was cell line of human acute lymphoblastic lymphoma    T cells, was incubated in RPMI1640 culture medium containing 10%    fetal bovine serum to obtain 5×10⁸ MOLT-4 cells. The cells were    collected by centrifugation and suspended with 10 mL of buffer    solution A [25 mM of tris-HCl, 5 mM of 2-mercaptoethanol, 2 mM of    benzamidine, 2 mM of EDTA, 0.1 mM of 4-(2-aminoethyl)benzenesulfonyl    hydrochloride; pH 7.5], then homogenized by Polytron® homogenizer.    The homogenate were centrifuged under 25,000×G for 10 minutes at    4° C. The supernatant was separated and thus obtained supernatant    was further centrifuged under 100,000×G for 60 minutes at 4° C., and    then filtrated with 0.2 μm filter to obtain the soluble fraction.-   (2) The obtained soluble fraction was filled in equilibrium HiTrap Q    column (5 mL×2) with buffer solution A, and phosphodiesterase    fractions were eluted by 300 mL of buffer solution A with linear    gradient from 0 to 0.8 M NaCl concentration. 5 mL each of 60 eluents    were collected, and each eluents were examined for cyclic AMP    metabolic activities of phosphodiesterase. The fraction eluting with    about 350 mM NaCl concentration parts, where metabolic activities    were not inactivated by 10 μM of rolipram (selective inhibitor for    phosphodiesterase IV) and 10 μM of milrinone (selective inhibitor    for phosphodiesterase III), were collected as storage solution for    using to test PDE 7 inhibiting effect.-   (3) The tested compound having desired concentration was reacted in    the solution of 20 mM tris-HCl (pH 7.5), 1 mM of MgCl₂, 100M of    EDTA, 330 μg/mL of bovine serum albumin, 4 μg/mL of 5′-nucleotidase,    0.1 μCi of ³H-cAMP (0.064 μM of cAMP), 10 μM of rolipram in storage    solution of PDE 7 for 2 hours at 25° C. After the reaction,    suspension of Sephadex®-QAE in 10 mM of HEPES-Na (pH 7.0) was added    to the reaction mixture, and the mixture was left at rest for 5    minutes. Further, Sephadex®-QAE was added to the obtained    supernatant and the mixture was left at rest for 5 minutes, then,    the radioactivity of the solution was measured.-   (4) IC₅₀ was calculated as 50% inhibiting concentration of the    metabolic activities of phosphodiesterase VII of the tested    compound.

The compounds of the present invention selectively inhibit PDE 7 andtheir selectivities are more than 10 times compared to otherphosphodiesterase. Therefore, it is expected that the side effect of thecompounds of the present invention caused by other isozyme to be less.

For example, the selectivity against PDE 4 (phosphodiesterase IV) of thecompounds of the present invention was affirmed by means of thefollowing Biological Test.

Biological Test 2:

Methods for Evaluating the PDE 4 Inhibiting Effect

The PDE 4 (phosphodiesterase IV) inhibiting effect of the compounds ofthe present invention was performed by the following method, which wasmodified assay method described in Biochemical. Pharmacol. 48(6),1219-1223 (1994).

-   (1) The active fraction of PDE 4 (phosphodiesterase IV) was    obtained. That is, the livers obtained from three Balb/c mice (male,    12 weeks: obtainable from CLEA Japan, Inc.) were suspended with 30    mL of buffer solution B [20 mM of bis-tris, 5 mM of    2-mercaptoethanol, 2 mM of benzamidine, 2 mM of EDTA, 0.1 mM of    4-(2-aminoethyl)benzenesulfonyl hydrochloride, 50 mM of sodium    acetate; pH 6.5], then homogenized by Polytron® homogenizer. The    homogenate were centrifuged under 25,000×G for 10 minutes at 4° C.    The supernatant was separated and thus obtained supernatant was    further centrifuged under 100,000×G for 60 minutes at 4° C., and    then filtrated with 0.2 μm filter to obtain the soluble fraction.-   (2) The obtained soluble fraction was filled in equilibrium DEAE    sepharose column (1×10 cm) with buffer solution B, and    phosphodiesterase fractions were eluted by 120 mL of buffer solution    B with linear gradient from 0.05 to 1M sodium acetate concentration.    5 mL each of 24 eluents were collected, and each eluents were    examined for cyclic AMP metabolic activities of phosphodiesterase.    The fraction eluting with about 620 mM of sodium acetate    concentration parts, where metabolic activities were inactivated by    30 μM of rolipram (selective inhibitor for phosphodiesterase IV),    were collected as storage solution to test PDE 4 inhibiting effect.-   (3) The tested compound having desired concentration was reacted in    the solution of 20 mM tris-HCl (pH 7.5), 1 mM of MgCl₂, 100 μM of    EDTA, 330 μg/mL of bovine serum albumin, 4 μg/mL of 5′-nucleotidase,    0.1 μCi of 3H-cAMP (0.064 μM of CAMP), and storage solution of PDE 4    for 2 hours at 25° C. After the reaction, suspension of    Sephadex®-QAE in 10 mM of HEPES-Na (pH 7.0) was added to the    reaction mixture, and the mixture was left at rest for 5 minutes.    Further, Sephadex®-QAE was added to the obtained supernatant and the    mixture was left at rest for 5 minutes, then, the radioactivity of    the solution was measured.-   (4) IC₅₀ was calculated as 50% inhibiting concentration of the    metabolic activities of phosphodiesterase IV of the tested compound.

As the results of the mentioned above Biological Test 2, the IC₅₀ of thecompounds of PDE 4 inhibiting effect of the present invention was morethan 10 times weaker than that of PDE 7 inhibiting effect.

In the following Tables 1 to 4, the IC₅₀ values of PDE 7 inhibitingactivities and PDE 4 inhibiting activities were summarized.

TABLE 1 Compound PD7 PDE4 No. IC₅₀/μM IC₅₀/μM 10 0.027 1.8 11 0.019 2 120.053 5 14 0.088 3.7 16 0.034 2.2 20 0.033 >30 21 0.084 2.5 23 0.083 4.825 0.098 6.5 26 0.044 3 28 0.05 30 32 0.095 2.5 36 0.04 25 37 0.028 2 380.033 5 39 0.014 3.5 40 0.075 15 41 0.05 12 45 0.05 12 46 0.03 2 470.032 3.5 51 0.075 9.5 53 0.055 3.5 58 0.036 3.6 59 0.08 7 60 0.065 6.567 0.023 3.5 70 0.025 4.7 72 0.01 1.2 73 0.012 1 74 0.05 7 76 0.02 2 770.02 2 79 0.06 — 80 0.06 2.5 94 0.058 >30 99 0.099 5 100 0.037 >30

TABLE 2 Compound PDE7 PDE4 No. IC₅₀/μM IC₅₀/μM 101 0.03 1.3 102 0.0855.5 104 0.058 1.5 106 0.009 1.2 107 0.017 2 109 0.015 1 110 0.075 5.5111 0.01 >30 112 0.008 1.2 114 0.021 1.5 115 0.04 1.5 125 0.075 4 1320.088 10 133 0.009 1.8 135 0.053 7.4 141 0.022 1.6 142 0.014 2 147 0.0853 149 0.065 2 150 0.045 0.7 152 0.085 3 155 0.01 1.5 156 0.055 2 1590.035 1.6 162 0.07 2 163 0.014 0.9 165 0.02 0.65 166 0.016 1.3 167 0.0151 168 0.022 1.5 170 0.022 1.3 171 0.037 1.7 172 0.048 9.4 176 0.02 1.7177 0.013 1.6 179 0.0031 0.75 180 0.01 1.4 181 0.0086 0.86 184 0.00681.1 188 0.0065 0.7 190 0.0035 1.7 191 0.0089 0.98 196 0.09 7.5 197 0.0794.4

TABLE 3 Compound PDE7 PDE4 No. IC₅₀/μM IC₅₀/μM 199 0.056 5.8 200 0.0161.9 201 0.018 2.2 202 0.033 2.4 203 0.0061 1.4 205 0.091 14 206 0.05 3.8207 0.024 2.4 208 0.025 3.8 209 0.077 7.4 225 0.018 2 227 0.056 10 2280.051 5.8 230 0.023 7 234 0.013 2.1 235 0.017 2.8 236 0.02 2.7 2370.0078 — 238 0.0078 2.7 239 0.015 2.6 240 0.041 — 246 0.051 6.6 2470.0065 1.4 255 0.089 12 256 0.002 0.81 257 0.068 8.3 258 0.015 4.7 2600.037 4.5 261 0.028 1.9 262 0.028 3.8 263 0.054 3.5 264 0.081 6.3 2560.07 11 268 0.088 4.8 270 0.015 1.8 271 0.0089 2.1 273 0.014 1.6 2740.0099 1.7 275 0.004 1.2 277 0.032 7.8 280 0.017 1.9 302 0.06 6.1 3050.066 6.8 313 0.09 12 316 0.097 15 317 0.067 12

TABLE 4 Compound PDE7 PDE4 No. IC₅₀/μM IC₅₀/μM 323 0.071 6.3 325 0.034 4331 0.029 4.9 339 0.02 5.1 340 0.054 28 341 0.005 1.8 342 0.028 4.6 3490.078 2.8 358 0.071 11 360 0.057 7.9 365 0.041 3.9 366 0.049 3.6 3670.02 2.3 368 0.026 2.9 369 0.024 7.6 370 0.0087 4.1 371 0.017 3.6 3720.011 4 373 0.0045 3.4 375 0.0072 0.93 378 0.044 2.5 379 0.013 1.2 3800.056 1.5 381 0.022 0.67 382 0.025 0.62 383 0.074 2.4 395 0.019 1.4 3960.022 0.9 402 0.019 7.3 404 0.032 3.5 412 0.043 4.9 413 0.03 2.5 4140.035 2.8 415 0.093 5.1 416 0.017 1.3 417 0.063 7 419 0.029 5.7 4230.072 8.1 425 0.09 13 428 0.05 9.7 436 0.03 7.2 440 0.097 28

The compounds of the present invention inhibit PDE 7 selectively, andtherefore, enhance cellular CAMP level. Consequently, the compounds ofthe present invention are useful for treating various kinds of diseasessuch as allergic diseases, inflamatory diseases or immunologicaldiseases. For example, the compounds of the present invention are usefulfor treating or preventing the diseases such as bronchial asthma,chronic bronchitis, chronic obstructive pulmonary disease, allergicrhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis,rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus,inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis,sepsis, Crohn's disease, rejection for organ transplantation, GVHdisease, and restenosis after angioplasty.

The compounds of the present invention can be used for preparation ofthe pharmaceutical composition or PDE 7 inhibitor. As an activeingredient, one or more compounds may be administered in theappropriated formulation. The formulation for oral administration mayinclude for example, capsules, granules, fine granules, syrups, drysyrups or the like; the formulation for parenteral administration mayinclude, for example injectable solution, suppository formulation suchas rectal suppository or vaginal suppository, nasal administration suchas sprays, or percutaneous absorption formulation such as ointment andtapes, and the like.

The administration dose may vary depending on the various kinds offactors. These factors may be the condition of the patients, theseverity of the diseases, ages, existence of a complication, as well asformulation. A usual recommended daily dose for oral administration iswithin the range of 0.1-1,000 mg/day/adult, preferably 0.1-500mg/day/adult, and more preferably 1-100 mg/day/adult. In the case ofparenteral administration, a usual recommended daily dose is within therange of 1/10 to ½ based on dose of oral administration. These doses canbe adjusted depending on age, as well as the patient's condition.

The toxicological properties of the compounds of the present inventionis low, therefore, the compounds of the present invention is expected tohave high safety margin.

EXAMPLES AND MANUFACTURING EXAMPLES

The compounds of the present invention and intermediate compounds usedfor the synthesis of the compounds of the present invention areillustrated in the following Manufacturing Examples and Examples.

The physicochemical data and chemical structure of the compounds aresummarized in the Tables mentions later. The compound numbers in theExamples and Manufacturing Examples are identical to those in theTables.

Manufacturing Example 1 tert-Butyl 5-nitro-1-indolinecarboxylate

To a solution of 500 mg (3.05 mmol) of 5-nitroindoline in 10 mL ofanhydrous dichloromethane was added 798 mg (3.65 mmol) of di-tert-butyldicarbonate under ice cooling, and the mixture was stirred for 1.5hours. Then, to this mixture was added catalytic amount of4-dimethylaminopyridine and the mixture was stirred for 1 hour at roomtemperature. Water was added to the reaction mixture and the mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline solution and dried over with anhydrous sodium sulfate.The solvent was removed under reduced pressure and the resulting residuewas purified by silica gel column chromatography (eluent: hexane/ethylacetate=6/1) to give 800 mg (99%) of the title compound.

Manufacturing Example 2 tert-Butyl 5-amino-1-indolinecarboxylate

80 mg of 10% palladium-carbon was added to a solution of 760 mg (2.88mmol) of the compound obtained in the Manufacturing Example 1 in 60 mLof methanol, and the reaction atmosphere was exchanged to hydrogen gasatmosphere. Then, the mixture was stirred for 30 minutes at roomtemperature and filtrated by Celite®. The filtrate was removed underreduced pressure to give 670 mg (99%) of the title compound.

Manufacturing Example 3 tert-Butyl 5-(acetylamino)-1-indolinecarboxylate

To a solution of 300 mg (1.28 mmol) of the compound obtained in theManufacturing Example 2 in 10 mL of anhydrous dichloromethane were added191 μL (2.69 mmol) of acetyl chloride and 375 μL (2.69 mmol) oftriethylamine, and the mixture was stirred for 1 hour at roomtemperature. Then, water was added to the reaction mixture and themixture was extracted with dichloromethane. The organic layer was driedover with anhydrous sodium sulfate and removed under reduced pressure.The resulting residue was purified by silica gel column chromatography(eluent: hexane/ethyl acetate=1/1 to 1/2) to give 370 mg (quantitative)of the title compound.

Manufacturing Example 4 N-(2,3-Dihydro-1H-indo-5-yl)acetamide HCl salt

A mixture solution of 330 mg (1.19 mmol) of the compound obtained in theManufacturing Example 3 in 15 mL of 4M-HCl/dioxane was stirred for 1.5hours at room temperature. Then, diethyl ether was added to the reactionmixture and the resulting precipitates were collected to give 173 mg(68%) of the title compound.

Manufacturing Example 5 6-Amino-N-isopropylnicotinamide

To a solution of 300 mg (2.17 mmol) of 6-aminonicotinic acid in 50 mL ofchloroform were added 370 μL (4.34 mmol) of isopropylamine, 4 mL ofanhydrous propanephosphonic acid (25 wt % solution in ethyl acetate) and1.4 mL (10 mmol) of triethylamine, and the mixture was stirred for 6hours at room temperature. Then, saturated sodium bicarbonate aqueoussolution was added to the reaction mixture, and the mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline solution and dried over with anhydrous sodium sulfate.The solvent was removed under reduced pressure and the residue waspurified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1 to 5/1) to give 30 mg (8%) of the titlecompound.

Manufacturing Example 6 1-(Methylsulfonyl)-5-nitroindoline

To a solution of 300 mg (1.83 mmol) of 5-nitroindoline in 20 mL ofdichloromethane were added 141 μL (2.74 mmol) of methanesulfonylchloride and 382 μL (2.74 mmol) of triethylamine, and the mixture wasstirred for 2 hours at room temperature. 141 μL (2.74 mmol) ofmethanesulfonyl chloride and 255 μL (1.83 mmol) of triethylamine werefurther added to the reaction mixture, and the mixture was stirred for 2hours at room temperature. Then, water was added to the reaction mixtureand the mixture was extracted with dichloromethane. The organic layerwas washed with saturated saline solution and dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was treated with diethyl ether, then, the precipitates werecollected by filtration to give 410 mg (92%) of the title compound.

Manufacturing Example 7 1-(Methylsulfonyl)-5-indolinamine

The title compound 150 mg (58%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 6, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 82-{4-[(4-Nitrophenyl)sulfonyl]-1-piperazinyl}ethanol

To a solution of 415 μL (3.38 mmol) of 1-piperazineethanol in 20 mL ofdichloromethane were added 500 mg (2.26 mmol) of 4-nitrobenzenesulfonylchloride and 472 μL (3.38 mmol) of triethylamine under ice cooling, andthe mixture was stirred for 30 minutes at the same temperature. Thereaction mixture was diluted with dichloromethane and the organic layerwas washed with water, saturated sodium bicarbonate aqueous solution andsaturated saline solution and then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 670 mg (94%) of the titlecompound.

Manufacturing Example 92-{4-[(4-Nitrophenyl)-sulfonyl]-1-piperazinyl}ethyl acetate

The title compound 175 mg (77%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in theManufacturing Example 8, instead of the compound obtained in theManufacturing Example 2.

Manufacturing Example 102-{4-(4-Aminophenyl)sulfonyl}-1-piperazinyl}ethyl acetate

The title compound 130 mg (95%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 9, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 11 tert-Butyltrans-4-(acetylamino)cyclohexylcarbamate

The title compound 130 mg (68%) was obtained in a manner similar to theManufacturing Example 3 by use of tert-butyltrans-4-amino-cyclohexylcarbamate, instead of the compound obtained inthe Manufacturing Example 2.

Manufacturing Example 12 N-(trans-4-Aminocyclohexyl)acetamidetrifluoroacetic acid salt

To a solution of 220 mg (0.86 mmol) of the compound obtained in theManufacturing Example 11 in 8 mL of dichloromethane was added 8 mL oftrifluoroacetic acid at room temperature, and the mixture was stirredfor 30 minutes at the same temperature. The reaction mixture wascondensed and the residue was treated with diethyl ether. The resultingprecipitates were collected by filtration to give 194 mg (84%) of thetitle compound.

Manufacturing Example 13 2-Methoxy-N-(4-nitrophenyl)acetamide

To a mixture solution of 384 μL (5.0 mmol) of methoxyacetic acid and 691mg (5.0 mmol) of p-nitroaniline in 10 mL of dichloromethane were added1.53 mg (5.5 mmol) of 2-chloro-1,3-dimethyl imidazoliumhexafluorophosphate and 1.53 mL (11.0 mmol) of triethylamine, and themixture was refluxed for 7 hours. Then, the reaction mixture wasextracted with ethyl acetate, the extract was washed with water andsaturated saline solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent: hexane/ethylacetate=2/1) to give 750 mg (71%) of the title compound.

Manufacturing Example 14 N-(4-Aminophenyl)-2-methoxyacetamide

The title compound 604 mg (86%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 13, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 15 6-(4-Methyl-1-piperazinyl)-3-pyridinylamine

The title compound 536 mg (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of1-methyl-4-(5-nitro-2-pyridinyl)piperazine, instead of the compoundobtained in the Manufacturing Example 1.

Manufacturing Example 16 1-Methyl-4-[(3-nitrophenyl)sulfonyl]piperazine

To a solution of 500 mg (2.26 mmol) of 3-nitrobenzenesulfonyl chloridein 30 mL of dichloromethane were added 275 μL (2.48 mmol) ofN-methylpiperazine and 786 μL (5.64 mmol) of triethylamine, and themixture was stirred for 1 hour at room temperature. The reaction mixturewas extracted with dichloromethane and the organic layer was washed withwater and saturated saline solution, and then, dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was treated with diethyl ether to give 510 mg (79%) of the titlecompound.

Manufacturing Example 17 3-[(4-Methyl-1-piperazinyl)sulfonyl]aniline

The title compound 350 mg (98%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 16, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 18 2-[2-Fluoro(methyl)-4-nitroanilino]ethanol

To a solution of 554 μL (5.0 mmol) of 3,4-difluoronitrobenzene in 10 mLof dimethyl sulfoxide were added 1.38 mg (10.0 mmol) of potassiumcarbonate and 803 μL (10.0 mmol) of 2-methylaminoethanol, and themixture was stirred for 1.5 hours at 100° C. The reaction mixture wascooled to room temperature and extracted with ethyl acetate, then, theextract was washed with water and saturated saline solution. After driedover with anhydrous sodium sulfate, the solvent was removed underreduced pressure ant the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=1/1) to give 1.06 g (99%)of the title compound.

Manufacturing Example 19 2-(4-Amino-2-fluoromethylanilino)ethanol

The title compound 900 mg (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of the compound obtainedin the Manufacturing Example 18, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 20 tert-Butyl4-(4-nitrophenyl)-1-piperidinecarboxylate

To a solution of 4.84 g (30 mmol) of 4-phenylpiperidine in 30 mL ofconc. sulfuric acid was added gradually a solution of 1.26 mL of fumingnitric acid in 5 mL of conc. sulfuric acid under ice cooling, and afteraddition, the reaction mixture was warmed up to room temperature. Then,the reaction mixture was poured into 200 g of ice and sodium hydroxideaqueous solution was added slowly until the mixture to be alkalified.The mixture was extracted with chloroform and the organic layer wasdried over with anhydrous sodium sulfate. The solvent removed underreduced pressure. Then, 2.18 g (10 mmol) of di-tert-butyl dicarbonatewas added to a solution of the resulting residue in 20 mL ofdichloromethane, and the mixture was stirred for 1 hour at roomtemperature. The mixture was concentrated and the residue was purifiedby silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 0.78 g (8%) of the titlecompound.

Manufacturing Example 21 tert-Butyl4-(4-aminophenyl)-1-piperidinecarboxylate

The title compound 392 mg (57%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 20, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 22 1-Ethyl-4-(2-fluoro-4-nitrophenyl)piperazine

The title compound 2.33 g (92%) was obtained in a manner similar to theManufacturing Example 18 by use of N-ethylpiperazine instead of2-methylaminoethanol.

Manufacturing Example 231-(2-Fluoro-4-nitrophenyl)-4-methyl-1,4-diazepam

The title compound 2.21 g (87%) was obtained in a manner similar to theManufacturing Example 18 by use of N-methylhomopiperazine, instead of2-methylaminoethanol.

Manufacturing Example 24 4-(4-Ethyl-1-perazinyl)-3-fluoroaniline

The title compound 1.85 g (94%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 22, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 25 1-(2-Fluoro-4-nitrophenyl)-4-methylpiperazine

To a solution of 3.9 mL (35 mmol) of 3,4-difluoronitrobenzene in 60 mLof dimethyl sulfoxide were added 9.7 mL (87.5 mmol) ofN-methylpiperazine and 12.1 g (87.5 mmol) of potassium carbonate, andthe mixture was refluxed for 5 hours at 100° C. The reaction mixture wascooled to room temperature and poured into 500 mL of ice water, and theresulting precipitates were collected. The collected precipitates weredissolved in 2M-HCl aqueous solution and washed with ether. The aqueouslayer was neutralized with 4M-NaOH aqueous solution to give theprecipitates. The precipitates were collected to give 5.71 g (68%) ofthe title compound.

Manufacturing Example 26 3-Fluoro-4-(4-methyl-1-piperazinyl)aniline

The title compound 2.76 g (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of the compound obtainedin the Manufacturing Example 25, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 278-(2-Fluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane

The title compound 2.82 g (quantitative) was obtained in a mannersimilar to the Manufacturing Example 25 by use of1,4-dioxa-8-azaspiro[4.5]decane, instead of N-methylpiperazine.

Manufacturing Example 284-(1,4-Dioxa-8-azaspiro[4.5]deca-8-yl)-3-fluoroaniline

To a solution of 2.0 g (7.09 mmol) of the compound obtained in theManufacturing Example 27 in 30 mL of methanol was added 200 mg ofplatinum on sulfide carbon, and the reaction atmosphere was changed tohydrogen gas atmosphere. Then, the mixture was stirred for 5 hours atnormal pressures and temperature. The react ion mixture was filtrated byCelite®, and the filtrate was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=3/1 to 1/1) to give 1.71 g (96%) of the titlecompound.

Manufacturing Example 298-(2-Chloro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane

The title compound 3.05 g (quantitative) was obtained in a mannersimilar to the Manufacturing Example 25 by use of3,4-dichloronitrobenzene and 1,4-dioxa-8-azaspiro[4.5]decane, instead of3,4-difluoronitrobenzene and N-methylpiperazine, respectively.

Manufacturing Example 303-Chloro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline

The title compound 1.84 g (85%) was obtained in a manner similar to theManufacturing Example 28 by use of the compound obtained in theManufacturing Example 29, instead of the compound obtained in theManufacturing Example 27.

Manufacturing Example 313-Fluoro-4-(4-dimethyl-1,4-diazapam-1-yl)aniline

The title compound 1.85 g (94%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 23, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 32 4-[2-(4-Morpholinyl)ethyl]aniline

The title compound 2.17 g (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of4-[2-(4-morpholinyl)-ethyl]nitrobenzene, instead of the compoundobtained in the Manufacturing Example 1.

Manufacturing Example 33 1-Methyl-3-(4-nitrobenzyl)-2,4-imidazolinedione

To a mixture solution of 685 mg (6.0 mmol) of 1-methylhydantoin in 10 mLof N,N-dimethylformamide and 10 mL of tetrahydrofuran was added 240 mg(6.9 mmol) of sodium hydride (60% oily) at room temperature, and themixture was stirred for 30 minutes at the same temperature. Then, 1.08 g(5.0 mmol) of p-nitrobenzyl bromide was added to the reaction mixture,and the mixture was stirred for over night at room temperature. Waterwas added to the reaction mixture and the mixture was extracted withethyl acetate. The organic layer was dried over with anhydrous sodiumsulfate and the solvent was removed under reduced pressure to give 1.38g (quantitative) of the title compound.

Manufacturing Example 34 3-(4-Aminobenzyl)-methyl-2,4-imidazolidinedione

To a mixture solution of 1.33 g (5.34 mmol) of the compound obtained inthe Manufacturing Example 33 in 12 mL of ethanol and 6 mL of conc.hydrochloric acid was added 5.41 g (24.01 mmol) of tin chloride (II)dehydrate at room temperature, and the mixture was stirred for 2 hoursat 75° C. The reaction mixture was cooled to room temperature, alkalizedby adding of 4N-sodium hydroxide aqueous solution and treated withchloroform. The mixture was filtered with Celite®, and chloroform layerwas separated and dried over with anhydrous sodium sulfate. The solventwas removed under reduced pressure to give 1.148 g (98%) of the titlecompound.

Manufacturing Example 35 tert-Butyl trans-4-cyanocyclohexylcarbamate

To a solution of 765 mg (4.99 mmol) of trans-4-cyanocyclohexanecarboxylic acid in 10 mL of tert-butanol was added 766 μL (5.49 mmol) oftriethylamine and 1.13 mL (5.24 mmol) of diphenylphosphorylazide at roomtemperature, and the mixture was refluxed for 6 hours. After thereaction mixture was cooled to room temperature, ethyl acetate was addedto this mixture and the organic layer was washed with saturated sodiumbicarbonate aqueous solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent: hexane/ethylacetate=2/1) to give 608 mg (54%) of the title compound.

Manufacturing Example 36 trans-4-Aminocyclohexane carbonitrile HCl salt

The title compound 361 mg (90%) was obtained in a manner similar to theManufacturing Example 4 by use of the compound obtained in theManufacturing Example 35, instead of the compound obtained in theManufacturing Example 3.

Manufacturing Example 37 1-(2-Aminoethyl)-4 methyl-2,3-piperazinedioneHCl salt

To a solution of 3.60 g (11.95 mmol) of2-[2-(4-methyl-2,3-dioxo-1-piperazinyl)ethyl]phthalimide in 30 mL ofethanol was added 695 μL (14.34 mmol) of hydrazine monohydrate and themixture was stirred at 40° C. for over night. The reaction mixture wascooled to room temperature, then, 25 mL of water and 6 mL of 6N—HCl wereadded to this mixture and the mixture was stirred for 5 hours at roomtemperature. After removed off the insoluble substances by filtration,the filtrate was concentrated and the residue was re-crystallized by 2%water-ethanol solution to give 2.12 g (85%) of the title compound.

Manufacturing Example 38 tert-Butyl1-[(dimethylamino)carbonyl]-4-piperidinylcarbamate

To a solution of 500 mg (2.50 mmol) of tert-butyl 4-piperidinylcarbamatein 20 mL of dichloromethane was added 522 μL (3.74 mmol) oftriethylamine and 276 μL (3.00 mmol) of dimethylaminocarbonyl chlorideand the mixture was stirred for 2 hours at room temperature. Then, themixture was treated with ethyl acetate and the organic layer was washedwith water and saturated saline solution, and then, dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureto give 636 mg (94%) of the title compound.

Manufacturing Example 39 4-Amino-N,N-dimethyl-1-piperidinecarboxamideHCl salt

The title compound 571 mg (quantitative) was obtained in a mannersimilar to the Manufacturing Example 4 by use of the compound obtainedin the Manufacturing Example 38, instead of the compound obtained in theManufacturing Example 3.

Manufacturing Example 40 tert-Butyl1-[(dimethylamino)sulfonyl]-4-piperidinecarbamate

To a solution of 412 mg (2.06 mmol) of tert-butyl 4-piperidinylcarbamatein 20 mL of dichloromethane were added 430 μL (3.09 mmol) oftriethylamine and 265 μL (2.47 mmol) of dimethylsulfamoyl chloride andthe mixture was stirred for 2 hours at room temperature. Then, themixture was treated with ethyl acetate and the organic layer was washedwith water and saturated saline solution, and then, dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/1) to give 536 mg (85%) of thetitle compound.

Manufacturing Example 41 4-Amino-N,N-dimethyl-1-piperidinesulfonamideHCl salt

The title compound 0.42 g (quantitative) was obtained in a mannersimilar to the Manufacturing Example 4 by use of the compound obtainedin the Manufacturing Example 40, instead of the compound obtained in theManufacturing Example 3.

Manufacturing Example 42 Methyl(2S,4S)-4-[tert-butoxycarbonyl]amino]-2-pyrrolidinecarboxylate

The title compound 4.70 g (96%) was obtained in a manner similar to theManufacturing Example 2 by using methyl(2S,4S)-1-benzyloxycarbonyl-4-tert-butoxycarbonylaminopyrrolidine-2-carboxylate,instead of the compound obtained in the Manufacturing Example 1.

Manufacturing Example 43 Methyl(2S,4S)-1-(aminocarbonyl)-4-[(tert-butoxycarbonyl)amino]-2-pyrrolidinecarboxylate

To a solution of 4.60 g (18.83 mmol) of the compound obtained in theManufacturing Example 42 in 80 mL of dioxane and 80 mL of water wereadded 2.29 g (28.55 mmol) of potassium isocyanate and 3.23 mL (56.49mmol) of acetic acid, and the mixture was stirred for 17 hour at roomtemperature. Then, the mixture was treated with ethyl acetate and theorganic layer was washed with water and saturated saline solution, andthen, dried over with anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=20/1) to give 2.32 g(43%) of the title compound.

Manufacturing Example 44 tert-Butyl(6S,7aS)-1,3-dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-ylcarbamate

To a solution of 2.21 g (7.69 mmol) of the compound obtained in theManufacturing Example 43 in 150 mL of methanol was added gradually 615mg (15.38 mmol) of sodium hydride (60% oily) and the mixture was stirredfor minutes at room temperature. After condensed the reaction mixture,ethyl acetate and diluted hydrochloric acid were added to this mixture.The organic layer was separated and dried over with anhydrous sodiumsulfate, and the solvent removed under reduced pressure to give 1.8 g(92%) of the title compound.

Manufacturing Example 45(6S,7aS)-6-Aminotetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione HClsalt

The title compound 1.18 g (91%) was obtained in a manner similar to theManufacturing Example 4 by use of the compound obtained in theManufacturing Example 44, instead of the compound obtained in theManufacturing Example 3.

Manufacturing Example 46 1-(5-Amino-2-pyridinyl)-2-imidazolidinone

The title compound 730 mg (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of1-(5-nitro-2-pyridinyl)-2-imidazolidinone, instead of the compoundobtained in the Manufacturing Example 1.

Manufacturing Example 47 3-(4-Aminophenyl)-2,4-imidazolidinedione

The title compound 179 mg (69%) was obtained in a manner similar to theManufacturing Example 2 by use of3-(4-nitrophenyl)-2,4-imidazolidinedione, instead of the compoundobtained in the Manufacturing Example 1.

Manufacturing Example 483-(4-Aminophenyl)-1-methyl-2,4-imidazolidinedione

The title compound 413 mg (95%) was obtained in a manner similar to theManufacturing Example 2 by use of3-(4-nitrophenyl)-1-methyl-2,4-imidazolidinedione, instead of thecompound obtained in the Manufacturing Example 1.

Manufacturing Example 49 (3R)-1-(4-Aminophenyl)-3-pyrrolidinol

The title compound 1.98 g (quantitative was obtained in a manner similarto the Manufacturing Example 2 by use of(3R)-1-(4-nitrophenyl)-3-pyrrolidinol, instead of the compound obtainedin the Manufacturing Example 1.

Manufacturing Example 50 (3R)-1-(2-Fluoro-4-nitrophenyl)-3-pyrrolidinol

The title compound 2.19 g (65%) was obtained in a manner similar to theManufacturing Example 18 by use of (R)-3-pyrrolidinol, instead of2-methylaminoethanol.

Manufacturing Example 51 (3R)-1-(4-Amino-2-fluorophenyl)-3-pyrrolidinol

The title compound 1.81 g (99%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 50, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 52 1-[(3-Nitrophenyl)sulfonyl]-4-piperidinol

The title compound 1.91 g (49%) was obtained in a manner similar to theManufacturing Example 16 by use of 4-hydroxypiperidine, instead ofN-methylpiperazine.

Manufacturing Example 53 1-[(3-Aminophenyl)sulfonyl]-4-piperidinol

The title compound 1.56 g (52%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 52, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 54 1-[(4-Nitrophenyl)sulfonyl]-4-piperidinol

The title compound 1.91 g (49%) was obtained in a manner similar to theManufacturing Example 8 by use of 4-hydroxypiperidine, instead of1-piperazineethanol.

Manufacturing Example 554-{[tert-Butyl(dimethyl)silyl]oxy}-1-[(4-nitrophenyl)sulfonyl]-piperidine

To a solution of 1.5 g (5.24 mmol) of the compound obtained in theManufacturing Example 54 in 60 mL of dichloromethane was added 1.32 mL(5.76 mmol) of tert-butyldimethylsilyl trifluorate at 0° C., and themixture was stirred overnight at room temperature. After the reaction,the reaction mixture was washed with water and the organic layer wasdried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=5/1) to give 2.04 g (97%)of the title compound.

Manufacturing Example 564-[(4-{[tert-Butyl(dimethyl)silyl]oxy}-1-piperidinyl)sulfonyl]-aniline

The title compound 1.67 g (98%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 55, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 571-Methyl-4-[4-nitro-2-(trifluoromethyl)phenyl]piperazine

The title compound 2.28 g (82%) was obtained in a manner similar to theManufacturing Example 25 by use of 2-fluoro-5-nitrobenzotrifluoride,instead of 3,4-difluoronitrobenzene.

Manufacturing Example 584-(4-Methyl-1-piperidinyl)-3-(trifluoromethyl)phenylamine

The title compound 1.96 g (99%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 57, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 592-[2-(5-Methyl-1,1-dioxide-1,2,5-thiadiazolidin-2-yl)ethyl]-1H-isoindole-1,3(2H)-dione

To a solution of 686 mg (5.04 mmol) of 2-methyl-1,2,5-thiadiazolidine1,1-dioxide in 10 mL of N,N-dimethylformamide was added 212 mg (5.30mmol) of sodium hydride (60% oily) at room temperature, and the mixturewas stirred for 1 hour at the same temperature. Then, 1.41 g (5.54 mmol)of N-(2-bromoethyl)phthalimide was added to the reaction mixture, andthe mixture was stirred for 1.5 hours at 75° C. After the reaction,water was added to the reaction mixture and solvent was removed underreduced pressure. The resulting residue was treated with water andextracted with dichloromethane and the organic layer was washed withwater and saturated saline solution, then, dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/5), and solidified by treating with ethylacetate/ether to give 526 mg (34%) of the title compound.

Manufacturing Example 602-(5-Methyl-1-1-dioxide-1,2,5-thiadiazolidin-2-yl)ethanamine HCl salt

To a suspension of 500 mg (1.62 mmol) of the compound obtained in theManufacturing Example 59 in 5 mL of ethanol was added 94 μL (1.94 mmol)of hydrazine monohydrate, and the mixture was stirred for 6 hours at 70°C. Then, insoluble substances were removed off by filtration and thefiltrate was removed under reduced pressure, and 5 mL of water and 1.5mL of 6M-HCl aqueous solution were added to the residue. Then, themixture was stirred for 6 hours at room temperature and insolublesubstances were removed off by filtration and the filtrate was removedunder reduced pressure. The resulting residue was recrystallized fromethanol to give 287 mg (82%) of the title compound.

Manufacturing Example 61 1-(2-Fluoro-4-nitrophenyl)-4-piperidinol

To a solution of 4.77 g (30.0 mmol) of 3,4-difluoronitrobenzene in 100mL of N,N-dimethylformamide were added 5.33 g (40.0 mmol) of potassiumcarbonate and 3.03 g (30.0 mmol) of 4-hydroxypiperidine and the mixturewas stirred for 1 hour at 120° C. After the reaction mixture was cooledto room temperature, the reaction mixture was diluted with chloroformand insoluble substances were removed off by filtration. The filtratewas condensed and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=1.5/1) to give 3.1 g (43%)of the title compound.

Manufacturing Example 62 1-(4-Amino-2-fluorophenyl)-piperidinol

To a solution of 2.95 g (12.28 mmol) of the compound obtained in theManufacturing Example 61 in 100 mL of ethanol was added 600 mg of5%-palladium carbon, and the atmosphere was exchanged to hydrogenatmosphere. The mixture was stirred for 2 hours at room temperature andfiltered. The filtrate was removed under reduced pressure to give 2.48 g(96%) of the title compound.

Manufacturing Example 63 tert-Butyltrans-4-(4-morpholinyl)cyclohexylcarbamate

To a solution of 21.43 g (0.1 mol) of tert-butylN-(trans-4-aminocyclohexyl)carbamate in 250 mL of N,N-dimethylformamidewere added 16.76 mL (0.12 mol) of bis(2-bromoethyl)ether and 34.85 mL(0.25 mol) of triethylamine, and the mixture was stirred for 6 hours at70° C. Then solvent was removed under reduced pressure and the residuewas treated with ethyl acetate. The organic layer was washed with sodiumcarbonate aqueous solution and saturated saline solution, then, driedover with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: chloroform alone to chloroform/methanol=30/1) togive 19.92 g (70%) of the title compound.

Manufacturing Example 64 trans-4-(4-Morpholinyl)cyclohexylamine di-HClsalt

To a solution of 18.53 g (65.16 mmol) of the compound obtained in theManufacturing Example 63 in 65 mL of chloroform was added 130 mL of4N—HCl/ethyl acetate solution, and the mixture was stirred for 3 hoursat room temperature. The reaction mixture was treated with 200 mL ofdiethyl ether and separated precipitates were collected to give 16.22 g(97%) of the title compound.

Manufacturing Example 65 4-(4-Nitrophenyl)-2-piperazinone

To a solution of 1.275 g (9.04 mmol) of 4-fluoronitrobenzene in 30 mL ofN,N-dimethylformamide were added 1.879 (13.56 mmol) of potassiumcarbonate and 905 mg (9.04 mmol) of piperazine-2-one, and the mixturewas stirred for 1 hour at 130° C. and for 1 hour at 140° C. The reactionmixture was cooled to room temperature and diluted with chloroform,then, insoluble substances were removed off by filtration. The filtratewas condensed under reduced pressure and the resulting solid was washedwith ethanol to give 859 mg (43%) of the title compound.

Manufacturing Example 66 4-(4-Aminophenyl)-2-piperidinone

The title compound 640 mg (89%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 65, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 67 3-Amino-N,N-dimethylbenzenesulfonamide

The title compound 2.55 g (99%) was obtained in a manner similar to theManufacturing Example 2 by use ofN,N-dimethyl-3-nitrobenzene-sulfonamide, instead of the compoundobtained in the Manufacturing Example 1.

Manufacturing Example 683-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]nitrobenzene

To a solution of 955 mg (4.13 mmol) of3-[(2-hydroxyethyl)sulfonyl]-nitrobenzene in 30 mL of dichloromethanewere added 747 mg (4.96 mmol) of tert-butyldimethylsilyl chloride and 10mg of 4-dimethylaminopyridine, and the mixture was stirred for overnight at room temperature. Then, the reaction mixture was diluted withdichloromethane and the organic layer was washed with water and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=4/1 to 2/1) to give 1.27 g(89%) of the title compound.

Manufacturing Example 693-[(2-tert-Butyl(dimethyl)silyl)oxy]ethyl)sulfonyl}aniline

The title compound 856 mg (94%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 68, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 702-[(2-Hydroxyethyl)(methyl)amino]-N-(4-nitrophenyl)acetamide

To a suspension of 2.946 g (13.73 mmol) of2-chloro-N-(4-nitrophenyl)acetamide in 30 mL of ethanol was added 3.31mL (41.18 mmol) of 2-(methylamino)ethanol and the mixture was refluxedfor 4 hours. After the reaction mixture was cooled to room temperatureand condensed, then, the residue was treated with ethyl acetate. Theorganic layer was washed with water and dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 2.05 g (59%) of the titlecompound.

Manufacturing Example 71 4-Methyl-(4-nitrophenyl)-2-piperazinone

To a solution of 1.48 g (5.84 mmol) of the compound obtained in theManufacturing Example 70 in 50 mL of tetrahydrofuran were added 1.75 mL(7.01 mmol) of tri-n-butylphosphine and 1.21 g (7.01 mmol) of1,1′-azobis-(N,N-dimethylformamide), and the mixture was stirred for 4hours at room temperature. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated saline solution and dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography to give 738 mg(54%) of the title compound.

Manufacturing Example 72 1-(4-Aminophenyl)-4 methyl-2-piperazinone

The title compound 545 mg (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of the compound obtainedin the Manufacturing Example 71, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 73 1-(5-Nitro-2-pyridinyl)-4-piperidinol

To a suspension of 1.0 g (6.3 mmol) of 2-chloro-5-nitropyridine in 20 mLof n-propanol was added 1.9 g (18.9 mmol) of 4-hydroxypiperidine, andthe mixture was stirred for 1.5 hours at 100° C. After cooling thereaction mixture, the solvent was removed under reduced pressure, andthe residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=50/1) to give 1.37 g (97%) of the titlecompound.

Manufacturing Example 74 1-(5-Amino-2-pyridinyl)-4-piperidinol

To a suspension of 1.35 g (6.04 mmol) of the compound obtained in theManufacturing Example 73 in 18 mL of ethanol and 3 mL of water wereadded 1.3 g of reduced iron and 0.25 mL of conc. hydrochloric acid, andthe mixture was stirred for 2 hours at 90° C. After cooling the reactionmixture, the mixture was filtrated by Celite® and filtrate was condensedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: dichloromethane/methanol=10/1) to give601 mg (51%) of the title compound.

Manufacturing Example 75 1-(2,3-Difluoro-4-nitrophenyl)-4-piperidinol

To a solution of 1.72 mL (15 mmol) of 2,3,4-trifluorobenzene inN,N-dimethylformamide were added 1.01 g (10 mmol) of 4-hydroxypiperidineand 2.3 mL (20 mmol) of 2,6-lutidine, and the mixture was stirred for 24hours at room temperature. The solvent was removed under reducedpressure, and saturated sodium bicarbonate aqueous solution was added tothe residue and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated saline solution, anddried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=2/1 to ethyl acetate alone)to give 1.82 g (70%) of the title compound.

Manufacturing Example 76 1-(4-Amino-2,3-difluorophenyl)-4-piperidinol

The title compound 1.23 g (78%) was obtained in a manner similar to theManufacturing Example 74 by use of the compound obtained in theManufacturing Example 75, instead of the compound obtained in theManufacturing Example 73.

Manufacturing Example 77 1-(2-Methyl-4-nitrophenyl)-4-piperidinol

To a solution of 1.55 g (10 mmol) of 2-fluoro-5-nitrotoluene in 35 mL ofN,N-dimethylformamide were added 1.01 g (10 mmol) of 4-hydroxypiperidineand 1.8 g (13 mmol) of potassium carbonate, and the mixture was stirredfor 2 hours at 120° C. The reaction mixture was poured into ice and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated saline solution, and dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to give 1.5 g (63%) of the title compound.

Manufacturing Example 78 1-(4-Amino-2-methylphenyl)-4-piperidinol

The title compound 1.2 g (quantitative) was obtained in a manner similarto the Manufacturing Example 2 by use of the compound obtained in theManufacturing Example 77, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 79 2-(4-Hydroxy-1-piperidinyl)-5-nitrobenzonitrile

The title compound 2.0 g (81%) was obtained in a manner similar to theManufacturing Example 77 by use of 2-fluoro-5-nitrobenzonitrile, insteadof 2-fluoro-5-nitrotoluene.

Manufacturing Example 80 5-Amino-2-(4-hydroxy-1-piperidin)benzonitrile

To a suspension of 1.0 g (4.04 mmol) of the compound obtained in theManufacturing Example 79 in 10 mL of water were added 790 mg (14.14mmol) of iron and 130 mg (2.42 mmol) of ammonium chloride, and themixture was refluxed for 3 hours. After the reaction mixture was cooledto room temperature, water was added to the reaction mixture, and themixture was extracted with chloroform. The organic layer was washed withwater and saturated saline solution, and dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1 to 1/4) to give 327 mg (37%) of the titlecompound.

Manufacturing Example 81 Methyl2-(4-hydroxy-1-piperidinyl)-5-nitrobenzoate

The title compound 2.30 g (98%) was obtained in a manner similar to theManufacturing Example 77 by use of methyl 2-fluoro-5-nitrobenzoate,instead of 2-fluoro-5-nitrotoluene.

Manufacturing Example 82 Methy5-amino-2-(4-hydroxy-1-piperidinyl)benzoate

The title compound 1.83 g (91%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in theManufacturing Example 81, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 83 tert-Butyl1-tetrahydro-2H-pyran-4-yl-4-piperidinylcarbamate

To a suspension of 9.5 g (184 mmol) of tert-butyl piperidin-4-ylcarbamate in 200 mL of 1,2-dichloroethane were added 4.4 mL (47.4 mmol)of tetrahydro-4H-pyran-4-one and 1.0 mL of acetic acid, and the mixturewas stirred for 30 minute. The reaction mixture was cooled to 0° C., andto this mixture was added 15 g (71.1 mmol) of sodiumtriacetoxyborohydride and the mixture was stirred for 4 hours at roomtemperature, then, 5.0 g (23.6 mmol) of sodium triacetoxyborohydride wasfurther added to the mixture and the mixture was stirred for 64 hours atroom temperature. Saturated sodium bicarbonate aqueous solution wasadded to the reaction mixture, and the mixture was extracted withdichloromethane. The organic layer was washed with water and saturatedsaline solution, and dried over with anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel column chromatography (eluent: hexane/ethyl acetate=2/1)to give 11.54 g (86%) of the title compound.

Manufacturing Example 84 1-Tetrahydro-2H-pyran-4-yl-4-piperidinaminedi-HCl salt

The title compound 10.8 g (quantitative) was obtained in a mannersimilar to the Manufacturing Example 4 by use of the compound obtainedin the Manufacturing Example 83, instead of the compound obtained in theManufacturing Example 3.

Manufacturing Example 85 tert-Butyl4-(4-{[(benzyloxy)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate

The title compound 4.0 g (96%) was obtained in a manner similar to theManufacturing Example 83 by use of benzyl 4-oxocyclohexylcarbamate andtert-butyl 1-piperazinecarbamate, instead of tetrahydro-4H-pyran-4-oneand tert-butyl piperidin-4-ylcarbamate, respectively.

Manufacturing Example 86 tert-Butyl4-(4-aminocyclohexyl)-1-piperazinecarboxylate

The title compound 2.6 g (quantitative) was obtained in a manner similarto the Manufacturing Example 2 by use of the compound obtained in theManufacturing Example 85, instead of the compound obtained in theManufacturing Example 1.

Manufacturing Example 87 (5-Amino-2-pyridinyl)methanol di-HCl salt

The title compound 686 mg (78%) was obtained in a manner similar to theManufacturing Example 4 by use of tert-butyl6-(hydroxylmethyl)pyridin-3-ylcarbamate, instead of the compoundobtained in the Manufacturing Example 3.

Manufacturing Example 88 tert-Butyltrans-4-[(chloroacetyl)amino]cyclohexylcarbamate

The title compound 604 mg (89%) was obtained in a manner similar to theManufacturing Example 3 by use of tert-butyltrans-4-aminocyclo-hexylcarbamate and chloroacetyl chloride, instead ofthe compound obtained in the Manufacturing Example 2 and acetylchloride, respectively.

Manufacturing Example 89 tert-Butyltrans-4-({[(2-hydroxyethyl)(methyl)amino]acetyl}amino)-cyclohexylcarbamate

To a suspension of 560 mg (1.93 mmol) of the compound obtained in theManufacturing Example 88 in 5 mL of ethanol was added 464 μL (5.78 mmol)of 2-(methylamino)ethanol and the mixture was refluxed for 1 hour. Aftercooling, the solvent was removed under reduced pressure and water wasadded to the residue, and the mixture was extracted withdichloromethane. The organic layer was washed with water and saturatedsaline solution, and dried over with anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby recrystallization (isopropanol) to give 391 mg (61%) of the titlecompound.

Manufacturing Example 90 tert-Butyltrans-4-(4-methyl-2-oxo-1-piperazinyl)cyclohexylcarbamate

589 mg (5.25 mmol) of potassium t-butoxide was added to a suspensionsolution of 560 mg (1.7 mmol) of the compound obtained in theManufacturing Example 89 in 10 mL of tetrahydrofuran, and a solution of499 mg (2.62 mmol) of p-toluenesulfonyl chloride in 5 mL oftetrahydrofuran was added to this mixture, then, the mixture was stirredfor 2 hours at 0° C. 499 mg (2.62 mmol) of p-toluenesulfonyl chlorideand 589 mg (5.25 mmol) of potassium t-butoxide were further added to thereaction mixture, and the mixture was stirred for 30 minutes at roomtemperature. Water was added to the reaction mixture and the mixture wasextracted with chloroform. The organic layer was washed with water andsaturated saline solution, and dried over with anhydrous sodium sulfate.The solvent was removed and the residue was purified by silica gelcolumn chromatography (eluent: dichloromethane/methanol=10/1) to give398 mg (75%) of the title compound.

Manufacturing Example 911-(trans-4-Aminocyclohexyl)-4-methyl-2-piperazinone di-HCl salt

The title compound 349 mg (quantitative) was obtained in a mannersimilar to the Manufacturing Example 4 by use of the compound obtainedin the Manufacturing Example 90, instead of the compound obtained in theManufacturing Example 3.

Manufacturing Example 92 Ethyl1-(4-{[(benzyloxy)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylate

The title compound 2.6 g (67%) was obtained in a manner similar to theManufacturing Example 83 by use of benzyl 4-oxocyclohexylcarbamate andethyl isonipecocotinate, instead of tetrahydro-4H-pyran-4-one andtert-butyl piperidin-4-ylcarbamate, respectively.

Manufacturing Example 93 Ethyl1-(4-aminocyclohexyl)-4-piperidinecarboxylate

The title compound 1.58 g (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of the compound obtainedin the Manufacturing Example 92, instead the compound obtained in theManufacturing Example 1.

Manufacturing Example 94 Ethyl 1-(4-nitrophenyl)-4-piperidinol

To a solution of 14.1 g (0.10 mol) of 4-fluoronitrobenzene in 200 mL ofN,N-dimethyl formamide were added 20.73 (0.15 mol) of potassiumcarbonate and 10.1 g (0.10 mol) of 4-hydroxypiperidine and the mixturewas stirred for 1 hour at 140° C. The reaction mixture was cooled toroom temperature and the mixture was treated with chloroform, theninsoluble substances were removed off by filtration. The filtrate wascondensed and the residue was recrystallized from ethanol to give 17.27g (78%) of the title compound.

Manufacturing Example 95 1-(Aminophenyl)-4-piperidinol

To a solution of 17.09 g (76.95 mmol) of the compound obtained in theManufacturing Example 94 in 300 mL of methanol was added 2.0 g of5%-palladium-carbon, and the atmosphere was exchanged to hydrogenatmosphere. The mixture was stirred for over night at room temperatureand the mixture was filtrated. The filtrate was removed under reducedpressure to give 13.04 g (88%) of the title compound.

Example 1 2-Cyclohexyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one

A mixture solution of 39.88 g (0.265 mol) of cyclohexylhydrazine HClsalt in 28.57 mL (0.265 mol) of methyl acetoacetate was heated for 1hour at 120° C. After the reaction mixture was cooled to roomtemperature, dichloromethane was added to this mixture and the mixturewas neutralized by 2N—NaOH aqueous solution. The organic layer was driedover with anhydrous sodium sulfate and the solvent was removed underreduced pressure. The resulting residue was treated with hexane to givecrystalline and the crystalline was collected by filtration to give33.84 g (71%) of the title compound.

Example 2 5-Chloro-1-cyclohexyl-3-methyl-1H-pyrazole

A mixture of 13.5 g (74.9 mmol) of the compound obtained in the Example1 and 13.5 mL of phosphorus oxychloride was heated for 2 hours at 110°C. Then, the reaction mixture was cooled to room temperature andcondensed under reduced pressure. The residue was extracted with ethylacetate, and the extract was washed with saturated sodium bicarbonateaqueous solution and saturated saline solution, then, dried over withanhydrous sodium sulfate. The solvent removed under reduced pressure togive 9.84 g (66%) of the title compound.

Example 3-1 5-Chloro-1-cyclohexyl-3-methyl-1H-pyrazole-4-carboxaldehyde

To a solution of 9.84 g (49.52 mmol) of the compound obtained in theExample 2 in 50 mL of N,N-dimethylformamide was added 11.5 mL (123.8mmol) of phosphorous oxychloride under ice cooling, and the mixture wasstirred for 30 minutes at room temperature and for 1 hour at 80° C.Then, the reaction mixture was cooled to room temperature and condensedunder reduced pressure. The residue was extracted with ethyl acetate andthe extract was washed with saturated sodium bicarbonate aqueoussolution and saturates saline solution, then, dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=10/1) to give 8.73 g (76%) of the title compound.

Example 3-2 5-Chloro-1-cyclohexyl-3-methyl-1H-pyrazole-4-carboxaldehyde

A mixture of 110 g (0.61 mol) of the compound obtained in the Example 1and 216 mL (2.32 mol) of phosphorus oxychloride was heated and stirredfor 2 hours at 110° C. Then, the reaction mixture was cooled to roomtemperature and added gradually to 630 mL of cooledN,N-dimethylformamide. After adding, the mixture was stirred for 30minutes at room temperature and for 5 hours at 80° C. The reactionmixture was cooled to room temperature, and the mixture was pouredslowly into ice. Chloroform was added to this mixture and pH of themixture was adjusted to about 4 by 4N—NaOH aqueous solution (about 2.3L). The organic layer was separated and water layer was extracted withchloroform. The combined organic layer was washed with water andsaturated saline solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/10 to 1/7) to give 100.8 g (73%) of the title compound.

Example 4 Ethyl[(1-cyclohexyl-4-formyl-3-methyl-1H-pyrazol-5-yl)sulfanil]-acetate

To a solution of 8.0 g (35.3 mmol) of the compound obtained in theExample 3 in 100 mL of acetonitrile were added 4.84 mL (44.11 mmol) ofethyl thioglycolate and 7.32 g (52.93 mmol) of potassium carbonate, andthe mixture was refluxed for 4 hours. Then, 1.93 mL (17.64 mmol) ofethyl thioglycolate and 2.43 g (17.64 mmol) of potassium carbonate werefurther added to the reaction mixture and the mixture was refluxed for 2hours. After the reaction mixture was cooled to room temperature andcondensed under reduced pressure. The residue was extracted with ethylacetate and the extract was washed with water and saturated salinesolution, then, dried over with anhydrous sodium sulfate. The solventwas removed under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: hexane/ethyl acetate=4/1) togive 8.09 g (74%) of the title compound.

Example 5-1 Ethyl1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate

To a solution of 7.95 g (25.61 mmol) of the compound obtained in theExample 4 in 100 mL of N,N-dimethylformamide were added 5.31 g (38.42mmol) of potassium carbonate and 677 mg (2.56 mmol) of 18-crown-6, andthe mixture was heated for 2 hours at 120° C. to 130° C. After coolingthe reaction mixture to room temperature, the mixture was extracted withethyl acetate, and the extract was washed with water and saturatedsaline solution, then, dried over with anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel column chromatography (eluent: hexane/acetone=15/1) togive 2.2 g (29%) of the title compound.

Example 5-2 Ethyl1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate

To a solution of 63.4 mL (0.578 mmol) of ethyl thioglycolate in 1 L oftetrahydrofuran was added gradually 23 g (0.578 mol) of sodium hydride(60% oily) under ice cooling, and the mixture was stirred for 1 hour atroom temperature. The reaction mixture was cooled with ice water, and asolution of 100.8 g (0.444 mol) of the compound obtained in the Example3 in 400 mL of tetrahydrofuran was added gradually to this reactionmixture during 45 minutes, and the mixture was stirred for 2 hours atroom temperature. Then, the reaction mixture was cooled with ice water,and 23 g (0.578 mol) of sodium hydride (60% oily) was added gradually tothis reaction mixture, and the mixture was stirred for 30 minutes at 0°C. After the reaction, the reaction mixture was poured slowly intoice/ethyl acetate solution, and the organic layer was separated. Thewater layer was extracted with ethyl acetate, and the combined organiclayer was washed with water and saturated saline solution, then driedover with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: ethyl acetate/hexane=1/8 to 1/5) to give 104.7 g(81%) of the title compound.

Example 6 1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylicacid

To a solution of 11.89 g (40.66 mmol) of the compound obtained in theExample 5 in 100 mL of ethanol was added 44.7 mL (44.7 mmol) of 1Nsodium hydroxide solution, and the mixture was heated for 1 hour at 60°C. Then, the reaction mixture was cooled to room temperature andcondensed under reduced pressure. Water and diethyl ether were added tothe residue and the water layer was separated. 23 mL of 2N—HCl aqueoussolution was added to the water layer, and the resulting precipitateswere collected to give 10.38 g (97%) of the title compound.

Example 7N-Benzyl-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 60 mg (0.23 mmol) of the compound obtained in theExample 6 in 2 mL of dichloromethane was added 33 μL (0.45 mmol) ofthionyl chloride, and the mixture was stirred for 8 hours at 80° C.Then, the solvent was removed under reduced pressure to give thecorresponding acid chloride intermediate compound.

Next, 27 μL (0.25 mmol) of benzylamine and 79 μL of triethylamine wereadded to the solution of the above acid chloride intermediate compoundin 2 mL of anhydrous dichloromethane under ice-cooling, and the mixturewas stirred for 1.5 hours at room temperature. Then, water was added tothe reaction mixture and the mixture was extracted with dichloromethane.The organic layer was dried over with anhydrous sodium sulfate andremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (eluent: hexane/ethyl acetate=4/1 to 3/1) to give75 mg (94%) of the title compound.

Example 81-Cyclohexyl-3-methyl-N-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 65 mg (84%) was obtained in a manner similar to theExample 7 by use of aniline, instead of benzylamine.

Example 9N-{4-[Acetyl(methyl)amino]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 89 mg (82%) was obtained in a manner similar to theExample 7 by use of N-(4-aminophenyl)-N-methylacetamide, instead ofbenzylamine.

Example 10N-[4-(Acetylamino)-3-methoxyphenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 73 mg (65%) was obtained in a manner similar to theExample 7 by use of N-(4-amino-3-methoxyphenyl)acetamide, instead ofbenzylamine.

Example 11N-(1-Acetyl-2,3-dihydro-1H-indo-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 30 mg (27%) was obtained in a manner similar to theExample 7 by use of 1-acetyl-2,3-dihydro-1H-indol-5-ylamine, instead ofbenzylamine.

Example 12 Ethyl4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}phenylcarbamate

The title compound 101 mg (89%) was obtained in a manner similar to theExample 7 by use of ethyl 4-aminophenylcarbamate, instead ofbenzylamine.

Example 13 tert-Butyl5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}-1-indolinecarboxylate

The title compound 133 mg (92%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example2, instead of benzylamine.

Example 141-Cyclohexyl-N-(2,3-dihydro-1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

The title compound 68 mg (99%) was obtained in a manner similar to theManufacturing Example 4 by use of the compound obtained in the Example13, instead of the compound obtained in the Manufacturing Example 3.

Example 151-Cyclohexyl-N-(1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 95 mg (95%) was obtained in a manner similar to theExample 7 by use of 5-aminoindole, instead of benzylamine.

Example 161-Cyclohexyl-3-methyl-N-[4-(4-morpholinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 85 mg (89%) was obtained in a manner similar to theExample 7 by use of 4-(4-morpholinyl)aniline, instead of benzylamine.

Example 171-Cyclohexyl-3-methyl-N-(3-nitrophenyl)-1H-thieno-[2,3-c]pyrazole-5-carboxamide

The title compound 175 mg (60%) was obtained in a manner similar to theExample 7 by use of 3-nitroaniline, instead of benzylamine.

Example 18N-(3-Aminophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 142 mg (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of the compound obtainedin the Example 17, instead of the compound obtained in the ManufacturingExample 1.

Example 19N-[3-(Acetylamino)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 60 mg (0.17 mmol) of the compound obtained in theExample 18 in 4 mL of anhydrous tetrahydrofuran were added 25 μL (0.35mmol) of acetyl chloride and 50 μL (0.35 mmol) of triethylamine underice cooling, and the mixture was stirred for 2 hour at room temperature.Then, water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was dried over withanhydrous sodium sulfate and removed under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane/ethylacetate=2/1 to 1/2) to give 15 mg (22%) of the title compound.

Example 201-Cyclohexyl-3-methyl-N-{4-(methylamino)carbonyl)phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 37 mg (41%) was obtained in a manner similar to theExample 7 by use of 4-amino-N-methylbenzamide, instead of benzylamine.

Example 211-Cyclohexyl-3-methyl-N-(1-propionyl-2,3-dihydro-1H-indol-5-yl)-1H-thieno-[2,3-c]pyrazole-5-carboxamide

The title compound 47 mg (75%) was obtained in a manner similar to theExample 19 by use of the compound obtained in the Example 14 andpropionyl chloride, instead of using the compound obtained in theExample 18 and acetyl chloride, respectively.

Example 22 Ethyl5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-indolinecarboxylate

The title compound 62 mg (82%) was obtained in a manner similar to theExample 19 by use of the compound obtained in the Example 14 and ethylchlorocarbonate, instead of the compound obtained in the Example 18 andacetyl chloride, respectively.

Example 231-Cyclohexyl-N-(1-isobutyl-2,3-dihydro-1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 68 mg (89%) was obtained in a manner similar to theExample 19 by use of the compound obtained in the Example 14 andisobutyryl chloride, instead of the compound obtained in the Example 18and acetyl chloride, respectively.

Example 24N-(1-Butyryl-2,3-dihydro-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 66 mg (87%) was obtained in a manner similar to theExample 19 by use of the compound obtained in the Example 14 andn-butyryl chloride, instead of the compound obtained in the Example 18and acetyl chloride, respectively.

Example 251-Cyclohexyl-N-[1-(2,2-dimethylpropanoyl)-2,3-dihydro-1H-indol-5-yl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 59 mg (76%) was obtained in a manner similar to theExample 19 by use of the compound obtained in the Example 14 andpropanoyl chloride, instead of the compound obtained in the Example 18and acetyl chloride, respectively.

Example 261-Cyclohexyl-3-methyl-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 60 mg (58%) was obtained in a manner similar to theExample 7 by use of 5-amino-1,3-dihydro-2H-indol-2-one, instead ofbenzylamine.

Example 27N-[4-(Acetylamino)-3-chlorophenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 28 mg (43%) was obtained in a manner similar to theExample 7 by use of N-(4-amino-2-chlorophenyl)acetamide, instead ofbenzylamine.

Example 281-Cyclohexyl-N-{4-[(ethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 30 mg (32%) was obtained in a manner similar to theExample 7 by use of 4-amino-N-ethylbenzamide, instead of benzylamine.

Example 291-Cyclohexyl-N-[4-(methoxymethyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 62 mg (70%) was obtained in a manner similar to theExample 7 by use of 4-(methoxymethyl)aniline, instead of benzylamine.

Example 301-Cyclohexyl-N-[4-(hydroxymethyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 65 mg (76%) was obtained in a mariner similar to theExample 7 by use of (4-aminophenyl)methanol, instead of benzylamine.

Example 311-Cyclohexyl-3-methyl-N-[4-(morpholinylcarbonyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 88 mg (90%) was obtained in a manner similar to theExample 7 by use of 4-(4-morpholinylcarbonyl)aniline, instead ofbenzylamine.

Example 321-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 57 mg (53%) was obtained in a manner similar to theExample 7 by use of 4-[(4-methyl-1-piperazinyl)carbonyl]aniline, insteadof benzylamine.

Example 331-Cyclohexyl-3-methyl-N-{4-[(methylsulfonyl)amino]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 33 mg (33%) was obtained in a manner similar to theExample 7 by use of N-(4-aminophenyl)methanesulfonamide, instead ofbenzylamine.

Example 341-Cyclohexyl-3-methyl-N-{4-[(methylamino)sulfonyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 22 mg (22%) was obtained in a manner similar to theExample 7 by use of 4-amino-N-methylbenzenesulfonamide, instead ofbenzylamine.

Example 35N-{1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-2,3-dihydro-1H-indol-5-yl}acetamide

The title compound 76 mg (80%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example4, instead of benzylamine.

Example 361-Cyclohexyl-3-methy-N-{4-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 36 mg (32%) was obtained in a manner similar to theExample 7 by use of 4-[(4-methyl-1-piperazinyl)sulfonyl]aniline, insteadof benzylamine.

Example 371-Cyclohexyl-N-(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 50 mg (50%) was obtained in a manner similar to theExample 7 by use of 4-amino-N-(2-methoxyethyl)benzamide, instead ofbenzylamine.

Example 38N-(4-Acetylphenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 54 mg (62%) was obtained in a manner similar to theExample 7 by use of p-aminoacetophenone, instead of benzylamine.

Example 391-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 86 mg (92%) was obtained in a manner similar to theExample 7 by use of 4-amino-N,N-dimethylbenzamide, instead ofbenzylamine.

Example 40 Ethyl4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}benzoate

The title compound 80 mg (51%) was obtained in a manner similar to theExample 7 by use of ethyl 4-aminobenzoate, instead of benzylamine.

Example 414-{[(1-Cyclohexyl-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}benzoicacid

To a solution of 55 mg (0.13 mmol) of the compound obtained in theExample 40 in 8 mL, of ethanol was added 134 μL of 1M sodium hydroxidesolution, and the mixture was stirred for 1 hour at room temperature.Then, 20 mL of water was added to the reaction mixture and the waterlayer was washed with ethyl acetate. The water layer was neutralized byadding of 1M-HCl solution, and the resulting precipitates were collectedto give 33 mg (65%) of the title compound.

Example 421-Cyclohexyl-N-(2-methoxy-4-nitrophenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 73 mg (31%) was obtained in a manner similar to theExample 7 by use of 2-methoxy-4-nitroaniline, instead of benzylamine.

Example 43N-(4-Amino-2-methoxyphenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 22 mg (37%) was obtained in a manner similar to theManufacturing Example 2 by use of the compound obtained in the Example42, instead of the compound obtained in the Manufacturing Example 1.

Example 44N-[4-(Acetylamino)-2-methoxyphenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 27 mg (49%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example43, instead of the compound obtained in the Manufacturing Example 2.

Example 451-Cyclohexyl-N-{4-[(isopropylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 47 mg (49%) was obtained in a manner similar to theExample 7 by use of 4-amino-N-isopropylbenzamide, instead ofbenzylamine.

Example 461-Cyclohexyl-N-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 93 mg (72%) was obtained in a manner similar to theExample 7 by use of 4-amino-N-(2-hydroxyethyl)benzamide, instead ofbenzylamine.

Example 47N-[6-(Acetylamino)-3-pyridinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 33 mg (37%) was obtained in a manner similar to theExample 7 by use of N-(5-amino-2-pyridinyl)acetamide, instead ofbenzylamine.

Example 481-Cyclohexyl-N-(4-methoxyphenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 81 mg (96%) was obtained in a manner similar to theExample 7 by use of p-anisidine, instead of benzylamine.

Example 491-Cyclohexyl-N-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 65 mg (85%) was obtained in a manner similar to theExample 7 by use of cyclopentylamine, instead of benzylamine.

Example 50 N,1-Dicyclohex3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 82 mg (quantitative) was obtained in a manner similarto the Example 7 by use of cyclohexylamine, instead of benzylamine.

Example 51N-{4-[(tert-Butylamino)carbonyl]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 89 mg (89%) was obtained in a manner similar to theExample 7 by use of 4-amino-N-(tert-butyl)benzamide, instead ofbenzylamine.

Example 521-Cyclohexyl-N-{5-[(isopropylamino)carbonyl]-2-pyridinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 13 mg (20%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example5, instead of benzylamine.

Example 531-Cyclohexyl-N-[4-(formylamino)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 11 mg (19%) was obtained in a manner similar to theExample 7 by use of 4-aminophenylformamide, instead of benzylamine.

Example 54 tert-Butyl4-[(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}phenyl)sulfonyl]-1-piperazinecarboxylate

The title compound 71 mg (32%) was obtained in a manner similar to theExample 7 by use of tert-butyl4-[(4-aminophenyl)sulfonyl]-1-piperazinecarboxylate, instead ofbenzylamine.

Example 551-Cyclohexyl-3-methyl-N-[4-(1-piperazinylsulfonyl)phenyl]-1H-thieno[2,3-c]-pyrazole-5-carboxamideHCl salt

The title compound 30 mg (61%) was obtained in a manner similar to theManufacturing Example 4 by use of the compound obtained in the Example54, instead of the compound obtained in the Manufacturing Example 3.

Example 561-Cyclohexyl-3-methyl-N-[4-(4-morpholinylsulfonyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 14 mg (12%) was obtained in a manner similar to theExample 7 by use of 4-(4-morpholinylsulfonyl)aniline, instead ofbenzylamine.

Example 571-Cyclohexyl-3-methyl-N-[4-(methylsulfonyl)phenyl]-1H-thieno[2,3-c]-pyrazole-5-carboxamide

The title compound 41 mg (43%) was obtained in a manner similar to theExample 7 by use of 4-(methylsulfonyl)aniline, instead of benzylamine.

Example 581-Cyclohexyl-N-[1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indol-5-yl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 42 mg (49%) was obtained in a manner similar to theExample 19 by use of the compound obtained in the Example 14 andcyclopropanecarbonyl chloride, instead of the compound obtained in theExample 18 and acetyl chloride, respectively.

Example 591-Cyclohexyl-3-methyl-N-[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 106 mg (quantitative) was obtained in a mannersimilar to the Example 7 by use of the compound obtained in theManufacturing Example 7, instead of benzylamine.

Example 60N-(1-Acetyl-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 94 mg (97%) was obtained in a manner similar to theExample 7 by use of 1-acetyl-1H-indole-5-amine, instead of benzylamine.

Example 611-Cyclohexyl-N-cyclopropyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 67 mg (96%) was obtained in a manner similar to theExample 7 by use of cyclopropylamine, instead of benzylamine.

Example 62N-(1-Benzyl-4-piperidinyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 200 mg (81%) was obtained in a manner similar to theExample 7 by use of 1-benzyl-4-piperidinylamine, instead of benzylamine.

Example 631-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

To a solution of 180 mg (0.42 mol) of the compound obtained in theExample 62 in 4 mL of 1,2-dichloroethane was added 50 μL of1-chloroethyl chloroformate, and the mixture was refluxed for 2 hours.Then, the reaction mixture was cooled to room temperature and condensedunder reduced pressure. The residue was dissolved in 6 mL of methanoland the mixture was refluxed for 3 hours. After the reaction mixture wascooled to room temperature, the solvent was removed under reducedpressure. The residue was washed with ethyl acetate and the resultingprecipitates were collected to give 109 mg (69%) of the title compound.

Example 64N-(1-Acetyl-4-piperidinyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 40 mg (78%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example63, instead of the compound obtained in the Manufacturing Example 2.

Example 65 Ethyl(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}phenoxy)acetate

The title compound 320 mg (96%) was obtained in a manner similar to theExample 7 by use of ethyl (4-aminophenoxy)acetate, instead ofbenzylamine.

Example 66(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}phenoxy)aceticacid

The title compound 268 mg (95%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 65, instead ofthe compound obtained in the Example 40.

Example 671-Cyclohexyl-3-methyl-N-{[(4-[2-(methylamino)-2-oxoethoxy]phenyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 24 mg (39%) was obtained in a manner similar to theManufacturing Example 5 by use of the compound obtained in the Example66 and methylamine (30%-methanol solution), instead of 6-aminonicoticacid and isopropylamine, respectively.

Example 68 Ethyl4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)-carbonyl]amino}phenyl)acetate

The title compound 223 mg (93%) was obtained in a manner similar to theExample 7 by use of ethyl(4-aminophenyl)acetate, instead of benzylamine.

Example 69(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}phenyl)aceticacid

The title compound 157 mg (84%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 68, instead ofthe compound obtained in the Example 40.

Example 701-Cyclohexyl-3-methyl-N-{4-[2-methylamino)-2-oxoethyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 31 mg (50%) was obtained in a manner similar to theManufacturing Example 5 by use of the compound obtained in the Example69 and methylamine (30%-methanol solution), instead of 6-aminonicoticacid and isopropylamine, respectively.

Example 71 tert-Butyl4-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}phenyl)-1-piperazinecarboxylate

The title compound 158 mg (quantitative) was obtained in a mannersimilar to the Example 7 by use of tert-butyl4-(4-aminophenyl)-1-piperazine-carboxylate, instead of benzylamine.

Example 721-Cyclohexyl-3-methyl-N-[4-(1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

The title compound 108 mg (88%) was obtained in a manner similar to theManufacturing Example 4 by use of the compound obtained in the Example71, instead of the compound obtained in the Manufacturing Example 3.

Example 73N-[4-(4-Acetyl-1-piperazinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 32 mg (63%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example72, instead of the compound obtained in the Manufacturing Example 2.

Example 741-Cyclohexyl-N-(trans-hydroxycyclohexyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 82 mg (quantitative) was obtained in a manner similarto the Example 7 by use of trans-4-aminocyclohexanol, instead ofbenzylamine.

Example 751-Cyclohexyl-3-methyl-N-(4-oxocyclohexyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 4.0 g (11.1 mmol) of the compound obtained in theExample 74 in 200 mL of dichloromethane was added 5.0 g (13.3 mmol) ofpyridinium dichromate, and the mixture was stirred for 6 hours at roomtemperature. Then, 5.0 g (13.3 mmol) of pyridinium dichromate wasfurther added to the reaction mixture and the mixture was stirred for 18hours. The reaction mixture was filtrated with Celite® and the filtratewas removed under reduced pressure. The residue was purified by silicagel column chromatography (eluent: dichloromethane/methanol=40/1) togive the 2.6 g (65%) of the title compound.

Example 761-Cyclohexyl-3-methyl-N-{4-[2-(4-methyl-1-piperazinyl)-2-oxoethexy]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 65 mg (90%) was obtained in a manner similar to theManufacturing Example 5 by use of the compound obtained in the Example66 and N-methylpiperazine, instead of 6-aminonicotic acid andisopropylamine, respectively.

Example 771-Cyclohexyl-N-{4-[2-(dimethylamino)-2-oxoethoxy]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 43 mg (67%) was obtained in a manner similar to theManufacturing Example 5 by use of the compound obtained in the Example66 and dimethylamine HCl salt, instead of 6-aminonicotic acid andisopropylamine, respectively.

Example 782-{4-[(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl-carbonyl]amino}phenyl)sulfonyl]-1-piperazinyl}ethylacetate

The title compound 60 mg (28%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example10, instead of benzylamine.

Example 791-Cyclohexyl-N-(4-{[4-(2-hydroethyl)-1-piperazinyl]sulfonyl}-phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 45 mg (0.08 mmol) of the compound obtained in theExample 78 in 4 mL of ethanol was added 86 μL of 1M sodium hydroxideaqueous solution, and the mixture was stirred for 1 hour at roomtemperature. Then, water was added to the reaction mixture and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated saline solution and dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 31 mg (74%) of the titlecompound.

Example 80N-[trans-4-(Acetylamino)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 28 mg (30%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example12, instead of benzylamine.

Example 811-Cyclohexyl-N,3-diethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 58 mg (92%) was obtained in a manner similar to theExample 7 by use of methylamine HCl salt, instead of benzylamine.

Example 82 2-Cyclopentyl 5-methyl-2,4-dihydro-3H-pyrazole-3-one

The title compound 9.70 g (80%) was obtained in a manner similar to theExample 1 by use of cyclopentylhydrazine HCl salt, instead ofcyclohexylhydrazine HCl salt.

Example 83 5-Chloro-1-cyclopentyl-3-methyl-1H-pyrazole

The title compound 4.5 g (81%) was obtained in a manner similar to theExample 2 by use of the compound obtained in the Example 82, instead ofthe compound obtained in the Example 1.

Example 84 5-Chloro-1-cyclopentyl-3-methyl-1H-pyrazole-4-carboxaldehyde

The title compound 4.0 g (79%) was obtained in a manner similar to theExample 3-1 by use of the compound obtained in the Example 83, insteadof the compound obtained in the Example 2.

Example 85 Ethyl[(1-cyclopentyl-4-formyl-3-methyl-1H-pyrazol-5-yl)sulfanil]-acetate

The title compound 1.9 g (36%) was obtained in a manner similar to theExample 4 by use of the compound obtained in the Example 84, instead ofthe compound obtained in the Example 3.

Example 86 Ethyl1-cyclopentyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxylate

The title compound 1.47 g (87%) was obtained in a manner similar to theExample 5-1 by use of the compound obtained in the Example 85, insteadof the compound obtained in the Example 4.

Example 87 1-Cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylicacid

The title compound 0.49 g (68%) was obtained in a manner similar to theExample 6 by use of the compound obtained in the Example 86, instead ofthe compound obtained in the Example 5.

Example 88N-[4-(Acetylamino)phenyl]-1-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 88 mg (72%) was obtained in a mariner similar to theExample 7 by use of N-(4-aminophenyl)acetamide and the compound obtainedin the Example 87, instead of benzylamine and the compound obtained inthe Example 6 respectively.

Example 89 2-Cycloheptyl-5-methyl-2,4-dihydro-3H-pyrazole-3-one

The title compound 16.27 g (52%) was obtained in a manner similar to theExample 1 by use of cycloheptylhydrazine HCl salt, instead of usingcyclohexylhydrazine HCl salt.

Example 90 5-Chloro-1-cycloheptyl-3-methyl-1H-pyrazole

The title compound 6.92 g (79%) was obtained in a manner similar to theExample 2 by use of the compound obtained in the Example 89, instead ofthe compound obtained in the Example 1.

Example 91 5-Chloro-1-cycloheptyl-3-methyl-1H-pyrazole-4-carboxaldehyde

The title compound 6.47 g (84%) was obtained in a manner similar to theExample 3-1 by use of the compound obtained in the Example 90, insteadof the compound obtained in the Example 2.

Example 92 Ethyl1-cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate

To a solution of 6.4 g (26.6 mmol) of the compound obtained in theExample 91 in 100 mL of acetonitrile were added 3.06 mL (27.9 mmol) ofethyl thioglycolate and 7.72 g (55.8 mmol) of potassium carbonate, andthe mixture was refluxed for 23 hours. Then, 3.06 mL (27.9 mmol) ofethyl thioglycolate was further added ant the mixture was refluxed for 3hours. After cooling the reaction mixture to room temperature, themixture was condensed and the residue was extracted withdichloromethane. The organic layer was washed with water and saturatedsaline solution, then, dried over with anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was purifiedby silica gel column chromatography (eluent: hexane/acetone=20/1) togive 2.46 g (30%) of the title compound.

Example 93 1-Cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylicacid

The title compound 1.40 g (67%) was obtained in a manner similar to theExample 6 by use of the compound obtained in the Example 92, instead ofthe compound obtained in the Example 5.

Example 94N-[4-(Acetylamino)phenyl]-1-cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 71 mg (60%) was obtained in a manner similar to theExample 7 by use of N-(4-aminophenyl)acetamide and the compound obtainedin the Example 93, instead of benzylamine and the compound obtained inthe Example 6, respectively.

Example 951-Cyclohexyl-N,3-dimethyl-N-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 103 mg (96%) was obtained in a manner similar to theExample 7 by use of N-methylaniline, instead of benzylamine.

Example 961-Cyclohexyl-3-methyl-N-(4-pyridinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 80 mg (96%) was obtained in a manner similar to theExample 7 by use of 4-aminopyridine, instead of benzylamine.

Example 971-Cyclohexyl-3-methyl-N-(3-pyridinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 48 mg (57%) was obtained in a manner similar to theExample 7 by use of 3-aminopyridine, instead of benzylamine.

Example 981-Cyclohexyl-3-methyl-N-(4-nitrophenyl)1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 170 mg (0.643 mmol) of the compound obtained in theExample 6 in 3 mL of 1,2-dichloroethane was added 94 μL (1.29 mmol) ofthionyl chloride, and the mixture was stirred for 1.5 hours at 90° C.After cooling the reaction mixture to room temperature, and the solventwas removed under the reduced pressure to give the corresponding acidchloride intermediate compound.

Then, to a solution of 170 mg (0.643 mmol) of 4-nitroaniline in 4 mL oftetrahydrofuran was added 77 mg (60% oily; 1.93 mmol) ofsodiumborohydride, and the mixture was stirred for 10 minutes at roomtemperature. Next, a solution of the above acid chloride in 3 mL oftetrahydrofuran was added to this mixture, and the mixture was stirredfor 30 minutes at room temperature. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated saline solution and dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureand the resulting solid was washed with methanol to give 150 mg (61%) ofthe title compound.

Example 99N-(4-Aminophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 142 mg (quantitative) was obtained in a mannersimilar to the Manufacturing Example 2 by use of the compound obtainedin the Example 98, instead of the compound obtained in the ManufacturingExample 1.

Example 100N-[4-(Acetylamino)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 10 mg (24%) was obtained in a manner similar to theExample 19 by use of the compound obtained in the Example 99, instead ofthe compound obtained in the Example 18.

Example 1011-Cyclohexyl-N-{4-[(methoxyacetyl)amino]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 92 mg (88%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example14, instead of benzylamine.

Example 102 Methyl5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-2-pyridinecarboxylate

The title compound 98 mg (43%) was obtained in a manner similar to theExample 7 by use of methyl 5-amino-2-pyridinecarboxylate, instead ofbenzylamine.

Example 1035-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-pyridinecarboxylicacid

The title compound 160 mg (87%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 102, insteadof the compound obtained in the Example 40.

Example 1041-Cyclohexyl-3-methyl-N-{6-[(methylamino)carbonyl]-3-pyridinyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 44 mg (77%) was obtained in a manner similar to theManufacturing Example 5 by use of the compound obtained in the Example103 and methylamine (30%-methanol solution), instead of 6-aminonicoticacid and isopropylamine, respectively.

Example 1051-Cyclohexyl-N-{6-[(dimethylamino)carbonyl]-3-pyridinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 50 mg (85%) was obtained in a manner similar to theManufacturing Example 5 by use of the compound obtained in the Example103 and dimethylamine HCl salt, instead of 6-aminonicotic acid andisopropylamine, respectively.

Example 1061-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 76 mg (77%) was obtained in a manner similar to theExample 7 by use of 4-(4-methyl-1-piperazinyl)aniline, instead ofbenzylamine.

Example 1071-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamidemethanesulfonate

To a suspension of 563 mg (1.287 mmol) of the compound obtained in theExample 106 in 5.6 mL of methanol was added 85.6 μL (1.319 mmol) ofmethanesulfonic acid at 50° C., and the mixture was refluxed. Then, thereact ion mixture was gradually cooled to 0° C. and the resultingprecipitates were collected to give 452 mg (66%) of the title compound.

Example 108N-(4-Cyanophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 300 mg (quantitative) was obtained in a mannersimilar to the Example 7 by use of 4-cyanoaniline, instead ofbenzylamine.

Example 1091-Cyclohexyl-3-methyl-N-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamidedi-HCl salt

1-Cyclohexyl-3-methyl-N-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide235 mg (79%) was obtained in a manner similar to the Example 7 by use of4-cyanoaniline, instead of benzylamine. Next, to a solution of 132 mg(0.301 mmol) of the above free base compound in 2 mL of methanol wasadded 166 μL of 4N—HCl/dioxane, and the mixture was diluted with diethylether. The resulting precipitates were collected to give 140 mg (91%) ofthe title compound.

Example 1101-Cyclohexyl-3-methyl-N-{3-[(4-methyl-piperazinyl)sulfonyl]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

1-Cyclohexyl-3-methyl-N-{3-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide133 mg (87%) was obtained in a manner similar to the Example 7 by use ofthe compound obtained in the Manufacturing Example 17, instead ofbenzylamine. Next, to a solution of 133 mg (0.265 mmol) of the abovefree base compound in 3 mL of methanol was added 80 μL of4N—HCl/dioxane, and the mixture was diluted with diethyl ether. Theresulting precipitates were collected to give 138 mg (97%) of the titlecompound.

Example 1111-Cyclohexyl-3-methyl-N-{3-[(methylamino)sulfonyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 45 mg (34%) was obtained in a manner similar to theExample 7 by use of 3-amino-N-methylbenzenesulfonamide, instead ofbenzylamine.

Example 1121-Cycloheptyl-3-methyl-N-[(4-(4-methyl-1-piperazinyl)phenyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 89 mg (78%) was obtained in a manner similar to theExample 106 by use of the compound obtained in the Example 93, insteadof the compound obtained in the Example 6.

Example 1131-Cyclohexyl-3-methyl-N-[(3-(4-methyl-1-piperazinyl)phenyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 106 mg (80%) was obtained in a manner similar to theExample 7 by use of 3-(4-methyl-1-piperazinyl)aniline, instead ofbenzylamine.

Example 1141-Cyclohexyl-N-[(4-(4-hydroxy-1-piperidinyl)phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 4.1 g (15.51 mmol) of the compound obtained in theExample 6 in 50 mL of 1,2-dichloroethane was added 2.26 mL (31.02 mmol)of thionyl chloride, and the mixture was refluxed for 1.5 hours. Aftercooling of the react ion and the solvent was removed under reducedpressure to give the corresponding acid chloride intermediate compound.

Then, 3.04 g (15.82 mmol) of the compound obtained in the ManufacturingExample 95 and 4.32 mL (31.02 mmol) of triethylamine were added to asolution of the above acid chloride intermediate compound in 150 mL ofanhydrous dichloromethane under ice cooling, and the mixture was stirredfor 20 hours at room temperature. Water was added to the reactionmixture, and the mixture was extracted with dichloromethane. The organiclayer was dried over with anhydrous sodium sulfate and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (eluent: dichloromethane/methanol=40/1 to 30/1) togive 7.5 g (83%) of the title compound.

Example 115N-[4-(Acetylamino)-3-methoxyphenyl]-1-cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 160 mg (59%) was obtained in a manner similar to theExample 10 by use of the compound obtained in the Example 93, instead ofthe compound obtained in the Example 6.

Example 1161-Cyclohexyl-N-(3,5-dichloro-4-pyridinyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 342 mg (88%) was obtained in a manner similar to theExample 98 by use of 4-amino-3,5-dichloropyridine, instead of4-nitroaniline.

Example 1175-[(4-Bromobenzyl)sulfanil]-1-cyclohexyl-3-methyl-1H-pyrazole-4-carboxaldehyde

To a solution of 1.2 g (5.29 mmol) of the compound obtained in theExample 3 in 21 mL of ethanol were added 2.07 g (6.35 mmol) ofS-(4-bromobenzyl)isothiourea hydrobromic acid salt and 10.6 mL of2N-sodium hydroxide solution, and the mixture was refluxed for 2 hours.After the reaction mixture was cooled to room temperature, the mixturewas condensed and the residue was diluted with ethyl acetate. Theorganic layer was washed with saturated saline solution and dried overwith anhydrous sodium sulfate. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=7/1) to give 1.723 g (82%)of the title compound.

Example 1185-(4-Bromophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole

To a solution of 1.623 g (4.13 mmol) of the compound obtained in theExample 117 in 30 mL of tetrahydrofuran was added gradually a solutionof 10.3 mL (10.3 mmol) of 1M lithium bis(trimethylsilyl)amide intetrahydrofuran at −78° C., and the mixture was stirred for 30 minutesat the same temperature. Then, the reaction mixture was warmed slowly to0° C. during 1 hour, and water was added to the reaction mixture. Themixture was extracted with dichloromethane and the organic layer wasdried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and 15 mL, of ethanol and 10 mL of 4N—HCl/dioxane wereadded to the residue and the mixture was stirred for 30 minutes at roomtemperature and for 30 minutes at 60° C. Then, the reaction mixture wascooled to room temperature and condensed under reduced pressure. Theresidue was diluted with ethyl acetate and the organic layer was washedwith saturated sodium bicarbonate aqueous solution, then, dried overwith anhydrous sodium sulfate. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=8/1) to give 717 mg (46%)of the title compound.

Example 1191-Cyclohexyl-3-methyl-5-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole

To a solution of 175 mg (0.466 mmol) of the compound obtained in theExample 118 in 30 mL of toluene were added 115 μL (1.40 mmol) ofN-methylpiperazine, 89.6 mg (0.933 mmol) of sodium tert-butoxide, 5.2 mg(0.023 mmol) of palladium acetate (II) and 9.4 mg (0.0466 mmol) oftri-tert-butyl-phosphine, and the mixture was refluxed for 5 hours.After the mixture was cooled to room temperature, ethyl acetate wasadded to the mixture and the organic layer was washed with water andsaturated saline solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 158 mg (86%) of the titlecompound.

Example 1201-Cyclohexyl-3-methyl-5-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazolemethanesulfonate

The title compound 143 mg (94%) was obtained in a manner similar to theExample 107 by use of the compound obtained in the Example 119, insteadof the compound obtained in the Example 106.

Example 1211-Cyclohexyl-3-methyl-5-[4-(4-methyl-1,4-diazepam-1-yl)phenyl]-1H-thieno[2,3-c]pyrazole

The title compound 124 mg (65%) was obtained in a manner similar to theExample 119 by use of N-methylhomopiperazine, instead ofN-methylpiperazine.

Example 1221-Cyclohexyl-N-(2-hydroxypropyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 82 mg (78%) was obtained in a manner similar to theExample 7 by use of 2-aminoethanol, instead of benzylamine.

Example 1231-Cyclohexyl-N-(3-hydroxypropyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 103 mg (94%) was obtained in a manner similar to theExample 7 by use of 3-amino-1-propanol, instead of benzylamine.

Example 124 1-Cyclohexyl-N-{3fluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 99 mg (68%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example19, instead of benzylamine.

Example 1251-Cyclohexyl-N-{3-fluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

To a solution of 91 mg (0.211 mmol) of the compound obtained in theExample 124 in 2 mL of diethyl ether and 1 mL of ethyl acetate was added63 μL (0.25 mmol) of 4N—HCl/1,4-dioxane, and 3 mL of diethyl ether wasfurther added to the mixture. The resulting precipitates were collectedto give 86 mg (87%) of the title compound.

Example 126 Ethylcis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclohexanecarboxylate

The title compound 365 mg (92%) was obtained in a manner similar to theExample 7 by use of ethyl cis-4-aminocyclohexanecarboxylate, instead ofbenzylamine.

Example 127cis-4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclohexanecarboxylicacid

The title compound 123 mg (88%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 126, insteadof the compound obtained in the Example 40.

Example 1281-Cyclohexyl-N-[cis-4-(hydroxymethyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 185 mg (0.433 mmol) of the compound obtained in theExample 126 in 6 mL of tetrahydrofuran were added 56 mg (1.33 mmol) oflithium chloride and 50 mg (1.33 mmol) of sodium borohydride, and themixture was stirred for 14 hours at room temperature. Then, ethylacetate was added to the mixture and the organic layer was washed withwater and saturated saline solution, then, dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/3) to give 110 mg (66%) of the title compound.

Example 129 Methyltrans-4-({[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}methyl)cyclohexanecarboxylate

The title compound 605 mg (96%) was obtained in a manner similar to theExample 7 by use of ethyl trans-4-aminocyclohexanecarboxylatehydrochloric acid salt, instead of benzylamine.

Example 1301-Cyclohexyl-N-methyl{[trans-4-(hydroxymethyl)cyclohexyl]methyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 150 mg (80%) was obtained in a manner similar to theExample 128 by use of the compound obtained in the Example 129, insteadof the compound obtained in the Example 126.

Example 131 tert-Butyltrans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexylcarbamate

The title compound 90 mg (quantitative) was obtained in a manner similarto the Example 7 by use of tert-butyl trans-4-aminocyclohexyl-carbamate,instead of benzylamine.

Example 132N-(trans-4-Aminocyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 890 mg (1.93 mmol) of the compound obtained in theExample 131 in 5 mL of N,N-dimethylformamide was added 9.66 mL of4N—HCl/dioxane, and the mixture was stirred for 3 hours at roomtemperature. Then, the mixture was diluted with dichloromethane and 50mL of 1N-sodium hydroxide solution was added to the mixture. The organiclayer was dried over with anhydrous sodium sulfate and the solvent wasremoved under reduced pressure. The residue was purified by alkalinesilica gel column chromatography (eluent: chloroform/methanol=60/1) togive 495 mg (71%) of the title compound.

Example 1331-Cyclohexyl-3-methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 120 mg (0.333 mmol) of the compound obtained in theExample 132 in 8 mL of N,N-dimethylformamide were added 46.8 μL (0.333mmol) of bis(2-chloroethyl)ether, 116 μL (0.832 mmol) of triethylamine,50 mg (0.333 mmol) of sodium iodide, and 6.5 μL (0.333 mmol) of15-crown-5, and the mixture was stirred for 24 hours at 100° C. Afterthe reaction mixture was cooled to room temperature, the mixture wasextracted with ethyl acetate and the organic layer was washed withsaturated sodium bicarbonate aqueous solution and saturated salinesolution, then, dried over with anhydrous sodium sulfate. The solventwas removed under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: chloroform/methanol=20/1) togive 22 mg (15%) of the title compound.

Example 1341-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

Saturated sodium bicarbonate solution and ethyl acetate were added tothe compound obtained in the Example 63, and the organic layer was driedover with anhydrous sodium sulfate. The solvent was removed and theresidue was purified by alkaline silica gel column chromatography(eluent: chloroform/methanol=60/1) to give 411 mg (60%) of the titlecompound.

Example 1351-Cyclohexyl-3-methyl-N-(1-tetrahydro-2H-pyran-4-yl-4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.433 mmol) of the compound obtained in theExample 134 in 8 mL of dichloromethane were added 44 μL (0.476 mmol) oftetrahydro-4-pyranone and 128 mg (0.606 mmol) of sodiumtriacetoxyborohydride, and the mixture was stirred for 24 hours at roomtemperature. Then, saturated sodium bicarbonate solution was added tothe reaction mixture and the mixture was extracted with dichloromethane.The organic layer was washed with water and saturated saline solution,then, dried over with anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=20/1) to give 70 mg(38%) of the title compound.

Example 1361-Cyclohexyl-N-[1-(1,4-diazaspiro[4.5]decan-8-yl)-4-piperazinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 180 mg (92%) was obtained in a manner similar to theExample 135 by use of 1,4-cyclohexanedione monoethyleneketal, instead oftetrahydro-4-pyranone.

Example 137 1-Cyclohexyl-3-methyl-N-[1-(4-oxocyclohexyl)-4piperidinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 153 mg (0.314 mmol) of the compound obtained in theExample 136 in 3 mL of acetone and 1 mL of water was added 71.8 mg(0.377 mmol) of p-toluenesulfonic acid monohydrate, and the mixture wasrefluxed for 2 days. Then, saturated sodium bicarbonate aqueous solutionwas added to the reaction mixture and the mixture was extracted withdichloromethane. The organic layer was dried over with anhydrous sodiumsulfate and removed under reduced pressure to give 120 mg (86%) of thetitle compound.

Example 1381-Cyclohexyl-N-[1-(trans-4-hydroxycyclohexyl)-4-piperidinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 109 mg (0.246 mmol) of the compound obtained in theExample 137 in 8 mL of ethanol was added 14.0 mg (0.369 mmol) of sodiumborohydride, and the mixture was stirred for 1 hour at 0° C. Then,dichloromethane was added to the reaction mixture and the organic layerwas washed with water, then, dried over with anhydrous sodium sulfate.The solvent was removed under reduced pressure and the residue waspurified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 67 mg (61%) of the titlecompound.

Example 139 tert-Butyl4-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-yl)carbonyl]amino}phenyl)-1-piperidinecarboxylate

The title compound 649 mg (quantitative) was obtained in a mannersimilar to the Example 7 by use of the compound obtained in theManufacturing Example 21, instead of benzylamine.

Example 1401-Cyclohexyl-3-methyl-N-[4-(4-piperidinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 584 mg (1.12 mmol) of the compound obtained in theExample 139 in 3 mL of dichloromethane was added 0.86 mL (11.2 mmol) oftrifluoroacetic acid at room temperature, and the mixture was stirredfor 1.5 hours at the same temperature. Then, the mixture was extractedwith dichloromethane and the organic layer was washed with 2N sodiumhydroxide solution and then, dried over with anhydrous sodium sulfate.The solvent was removed under reduced pressure and the residue waspurified by silica gel column chromatography (eluent:dichloromethane/methanol=100/1) to give 437 mg (92%) of the titlecompound.

Example 1411-Cyclohexyl-3-methyl-N-[4-(4-piperidinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

The title compound 94 mg (86%) was obtained in a manner similar to theExample 125 by use of the compound obtained in the Example 140, insteadof the compound obtained in the Example 124.

Example 1421-Cyclohexyl-3-methyl-N-[4(1-methyl-4-piperidinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 174 mg (0.412 mmol) of the compound obtained in theExample 140 in 5 mL of chloroform were added 31 μL (0.494 mmol) ofmethyl iodide and 86 μL (0.618 mmol) of triethylamine, and the mixturewas stirred for 2 hours at room temperature. Then, saturatedsodiumbicarbonate aqueous solution was added to the reaction mixture andthe mixture was extracted with dichloromethane. The organic layer wasdried over with anhydrous sodium sulfate and removed under reducedpressure. The residue was purified by alkaline silica gel columnchromatography (eluent: dichloromethane/methanol=40/1) to give 46 mg(26%) of the title compound.

Example 1431-Cyclohexyl-N-[4-(4-ethyl-1-piperazinyl)-3-fluorophenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 90 mg (42%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example24, instead of benzylamine.

Example 1441-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1,4-diazepam-1-yl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 161 mg (76%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example31, instead of benzylamine.

Example 145Ethyl-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino-2-methoxybenzoate

The title compound 401 mg (80%) was obtained in a manner similar to theExample 7 by use of ethyl 4-amino-2-methoxybenzoate, instead ofbenzylamine.

Example 1464-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-methoxybenzoicacid

The title compound 242 mg (59%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 145, insteadof the compound obtained in the Example 40.

Example 1471-Cyclohexyl-N-{3-methoxy-[(4-methyl-piperazinyl)carbonyl]-phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

To a solution of 200 mg (0.48 mmol) of the compound obtained in theExample 146 in 3 mL of anhydrous dichloromethane were added 64 μL (0.58mmol) of N-methylpiperazine and 111 mg (0.58 mmol) of1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide HCl salt, and the mixturewas stirred for 3 hours at room temperature. Then, saturated sodiumbicarbonate aqueous solution was added to the reaction mixture and themixture was extracted with dichloromethane. The organic layer was washedwith water and saturated saline solution and dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1 to 10/1). The obtained crude crystallinewas dissolved in 4M-HCl/dioxane and the solvent was removed underreduced pressure. The obtained solid was collected to give 124 mg (49%)of the title compound.

Example 1481-Cyclohexyl-N-[3-methoxy-4-(4-morpholinylcarbonyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 76 mg (79%) was obtained in a manner similar to theExample 147 by use of morpholine, instead of N-methylpiperazine.

Example 1491-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)carbonyl]phenyl}-3-methoxyphenyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 68 mg (69%) was obtained in a manner similar to theExample 147 by use of 4-hydroxypiperidine, instead ofN-methylpiperazine.

Example 1501-Cyclohexyl-N-(4-{[(2-hydroxyethyl)amino]carbonyl}-3-methoxyphenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 53 mg (58%) was obtained in a manner similar to theExample 147 by use of 2-aminoethanol, instead of N-methylpiperazine.

Example 1511-Cyclohexyl-N-(3-methoxy-4{[(2-methoxyethyl)amino]carbonyl}-phenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 73 mg (78%) was obtained in a manner similar to theExample 147 by use of 2-methoxyethylamine, instead ofN-methylpiperazine.

Example 1521-Cyclohexyl-N-{3-methoxy-4-[(methylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 31 mg (36%) was obtained in a manner similar to theExample 147 by use of methylamine HCl salt, instead ofN-methylpiperazine.

Example 1531-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]-3-methoxyphenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 70 mg (80%) was obtained in a manner similar to theExample 147 by use of dimethylamine HCl salt, instead ofN-methylpiperazine.

Example 1541-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 136 mg (79%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example26, instead of benzylamine.

Example 1551-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamidemethanesulfonic acid salt

A suspension of 100 mg (0.22 mmol) of the compound obtained in theExample 154 in 2 mL of methanol was heated at 50° C., and to thissuspension was added 14 mL (0.22 mmol) of methanesulfonic acid, then,the mixture was refluxed for 10 minutes. The reaction mixture was cooledgradually and the appeared precipitates were collected to give 68 mg(56%) of the title compound.

Example 156N-[3-Chloro-4-(4-methyl-1-piperazinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3]pyrazole-5-carboxamide

The title compound 169 mg (95%) was obtained in a manner similar to theExample 7 by use of 3-chloro-4-(4-methyl-1-piperazinyl)aniline, insteadof benzylamine.

Example 1571-Cyclohexyl-N-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-fluorophenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 546 mg (96%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example28, instead of benzylamine.

Example 1581-Cyclohexyl-N-[3-fluoro-4-(4-oxo-1-piperadinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 500 mg (1.00 mmol) of the compound obtained in theExample 157 in a mixture solution of 20 mL of toluene and 2 mL of waterwas added 229 mg (1.20 mmol) of p-toluenesulfonic acid monohydrate, andthe mixture was refluxed for 8 hours. Then, the react ion mixture wascooled to room temperature and condensed under reduced pressure.Saturated sodium bicarbonate aqueous solution was added to the residueand the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated saline solution, and then, dried overwith anhydrous sodium sulfate. The solvent was removed under reducedpressure to give 460 mg (quantitative) of the title compound.

Example 159-11-Cyclohexyl-N-[3-fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 150 mg (0.33 mmol) of the compound obtained in theExample 158 in anhydrous methanol was added 15 mg (0.39 mmol) of sodiumborohydride under ice cooling, and the mixture was stirred for 3 hoursat the same temperature and for 2 hours at room temperature. Then,acetone was added to the reaction mixture and the solvent was removedunder reduced pressure. The residue was diluted with ethyl acetate andthe organic layer was washed with water and saturated saline solution.The solvent was removed under reduced pressure and the residue waspurified by silica gel column chromatography (eluent: hexane/ethylacetate=1/2 to 0/1) to give 114 mg (76%) of the title compound.

Example 159-2

To a suspension of 900 mg (3.40 mmol) of the compound obtained in 15 mLof 1,2-dichloroethane was added 497 μL (6.81 mmol) of thionyl chloride,and the mixture was refluxed for 1.5 hours. After cooling the reactionmixture, the solvent removed under reduced pressure to give acidchloride intermediate compound.

Then, 752 mg (3.57 mmol) of the compound obtained in the ManufacturingExample 62 and 949 μL (6.81 mmol) of triethylamine were added to asolution of acid chloride intermediate compound obtained above in 40 mLof anhydrous dichloromethane, and the mixture was stirred for 6 hours atroom temperature. Water was added to the reaction mixture and themixture was extracted with dichloromethane. The organic layer was driedover with anhydrous sodium sulfate, and the solvent was removed underreduced pressure. The resulting residue was recrystallized from ethanolto give 0.86 g (55%) of the title compound.

Example 160N-[3-Chloro-4-(1,4-dioza-8-azaspiro[4.5]decan-8-yl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 565 mg (96%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example30, instead of benzylamine.

Example 161N-[3-Chloro-4-(4-oxo-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5carboxamide

The title compound 282 mg (61%) was obtained in a manner similar to theExample 158 by use of the compound obtained in the Example 160, insteadof the compound obtained in the Example 157.

Example 162N-[3-Chloro-4-(4-hydroxy-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 90 mg (90%) was obtained in a manner similar to theExample 159-1 by use of the compound obtained in the Example 161,instead of the compound obtained in the Example 158.

Example 1631-Cyclohexyl-N-{3-fluoro-4-[4-(methylamino)-1-piperidinyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 150 mg (0.33 mmol) of the compound obtained in theExample 158 in 3 mL of 1,2-dichloroethane were added 68 μL (0.66 mmol)of trimethylamine (30%-ethanol solution), 20 μL of acetic acid and 105mg (0.50 mmol) of sodium triacetoxyborohydride, and the mixture wasstirred for 18 hours at room temperature. Then, saturated sodiumbicarbonate solution was added to the reaction mixture and the mixturewas extracted with dichloromethane. The organic layer was washed withwater and saturated saline solution, and then, dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by alkaline silica gel column chromatography(eluent: dichloromethane/methanol=20/1) to give 148 mg (97%) of thetitle compound.

Example 164 tert-Butyl1-(2-chloro-4-{[(1-cyclohexyl-3-methyl-3-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}phenyl)-4-piperidinyl(methyl)carbamate

To a suspension of 200 mg (0.43 mol) of the compound obtained in theExample 161 in 3 mL of 1,2-dichloroethane were added 88 μL (0.85 mmol)of trimethylamine (30%-ethanol solution), 15 μL of acetic acid and 135mg (0.64 mmol) of sodium triacetoxyborohydride, and the mixture wasstirred for 4 hours at room temperature. Then, saturated sodiumbicarbonate solution was added to the reaction mixture and the mixturewas extracted with dichloromethane. The organic layer was washed withwater and saturated saline solution, the dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was dissolved in 4 mL of dichloromethane. To this mixture wereadded 186 mg (0.85 mmol) of tert-butyldicarbonate and 0.14 mL (1.02mmol) of triethylamine, and the mixture was stirred for 1 hour at roomtemperature. Water was added to the reaction mixture and the mixture wasextracted with dichloromethane. The organic layer was washed with waterand saturated saline solution and dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent: hexane/ethylacetate=1/1) to give 236 mg (95%) of the title compound.

Example 165N-{3-Chloro-4-[4-(methylamino)-1-piperidinyl]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 211 mg (0.36 mmol) of the compound obtained in theExample 164 in 3 mL of dichloromethane was added 1.5 mL oftrifluoroacetic acid, and the mixture was stirred for 1.5 hours at roomtemperature. After removal of the solvent under reduced pressure, waterwas added to the residue and the mixture was extracted with chloroform.The organic layer was washed with water and saturated saline solutionand dried over with anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the residue was purified by alkaline silicagel column chromatography (eluent=dichloromethane/methanol=40/1) to give116 mg (66%) of the title compound.

Example 1661-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-1-piperazinyl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.421 mmol) of the compound obtained in theExample 75 in 3 mL of dichloromethane were added 93 μL (0.84 mmol) ofN-methylpiperazine, 15 μL of acetic acid and 133 mg (0.63 mmol) ofsodium triacetoxyborohydride, and the mixture was stirred for 3 hours atroom temperature. Then, saturated sodium bicarbonate solution was addedto the reaction mixture and the mixture was extracted withdichloromethane. The organic layer was washed with water and saturatedsaline solution, then, dried over with anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby alkaline silica gel column chromatography (eluent: ethyl acetate) togive 103 mg (56%) of the title compound.

Example 1671-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-1,4-diazepam-1-yl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 101 mg (53%) was obtained in a manner similar to theExample 166 by use of N-methylhomopiperazine, instead ofN-methylpiperazine.

Example 1681-Cyclohexyl-N-[trans-4-(4-methoxyl-1-piperidinyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 30 mg (20%) was obtained in a manner similar to theExample 166 by use of 4-methoxypiperidine p-toluenesulfonic acid salt,instead of N-methylpiperazine.

Example 169 Benzyl4-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1,4-diazepam-1-carboxylate

The title compound 252 mg (78%) was obtained in a manner similar to theExample 166 by use of benzyl 1-homopiperazinecarboxylate, instead ofN-methylpiperazine.

Example 1701-Cyclohexyl-N-[trans-4-(1,4-diazepam-1-yl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

A mixture solution of 219 mg (0.38 mmol) of the compound obtained in theExample 169 in 3 mL of 30%-Hr/acetic acid was stirred for 3 hours atroom temperature. Then, the reaction mixture was neutralized by4M-sodium hydroxide aqueous solution and the mixture was extracted withdichloromethane. The organic layer was washed with water and saturatedsaline solution and dried over with anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby alkaline silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 126 mg (75%) of the titlecompound.

Example 171N-[trans-4-(4-Acetyl-1,4-diazepam-1-yl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 96 mg (99%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example170 and acetic anhydride, instead of the compound obtained in theManufacturing Example 2 and acetyl chloride, respectively.

Example 1721-cyclohexyl-N-{trans-4-[(2-methoxyethyl)(methyl)amino]-cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 131 mg (73%) was obtained in a manner similar to theExample 166 by use of N-(2-methoxyethyl)methylamine, instead ofN-methylpiperazine.

Example 1731-Cyclohexyl-N-{cis-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 34 mg (19%) was obtained as by-product in the Example172.

Example 1741-Cyclohexyl-N-[trans-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 664 mg (98%) was obtained in a manner similar to theExample 166 by use of 1,4-dioxa-8-azaspiro[4.5]decane, instead ofN-methylpiperazine.

Example 1751-Cyclohexyl-3-methyl-N-[trans-4-(4-oxo-1-piperidinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

A mixture of 384 mg (0.79 mmol) of the compound obtained in the Example174 in 6 mL of 6M-HCl aqueous solution was stirred for 9 days at roomtemperature. Then, the reaction mixture was neutralized by saturatedsodium bicarbonate aqueous solution and the mixture was extracted withchloroform. The organic layer was washed with water and saturated salinesolution, and dried over with anhydrous sodium sulfate. The solvent wasremoved under reduced pressure to give 317 mg (91%) of the titlecompound.

Example 1761-Cyclohexyl-N-[trans-4-(4-hydroxy-1-piperidinyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 102 mg (quantitative) was obtained in a mannersimilar to the Example 159 by use of the compound obtained in theExample 175, instead of the compound obtained in the Example 158.

Example 1771-Cyclohexyl-N-{trans-4-[(2R,6S)-2,6-dimethylmorpholinyl]-cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 126 mg (66%) was obtained in a manner similar to theExample 166 by use of cis-2,6-dimethylmorpholine, instead ofN-methylpiperazine.

Example 1781-cyclohexyl-N-{cis-4-[(2R,6S)-2,6-dimethylmorpholinyl]-cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 50 mg (26%) was obtained as by-product in the Example177.

Example 1791-Cyclohexyl-3-methyl-N-{trans-4-[4-(methylamino)-1-piperidinyl]-cyclohexyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 182 mg (89%) was obtained in a manner similar to theExample 166 by use of the compound obtained in the Example 175 andmethylamine (30% ethanol solution), instead of the compound obtained inthe Example 75 and N-methylpiperazine, respectively.

Example 180N-(trans-4-{4-[Acetyl(methyl)amino]-1-piperidinyl}cyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 35 mg (72%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example179 and acetic anhydride, instead of the compound obtained in theManufacturing Example 2 and acetyl chloride, respectively.

Example 1811-Cyclohexyl-N-{trans-4-[4-(dimethylamino)-1-piperidinyl]-cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a mixture solution of 70 mg (0.15 mmol) of the compound obtained inthe Example 179 in 2 mL of ethanol and 2 mL of water were added 30 mg ofparaformaldehyde and 1 mL of formic acid, and the mixture was refluxedfor 6 hours. Further 30 mg of paraformaldehyde and 1 mL of formic acidwere added to the reaction mixture, and the mixture was refluxed for 18hours. Then, the reaction mixture was cooled to room temperature andneutralized with saturated sodium bicarbonate aqueous solution, andextracted with dichloromethane. The organic layer was washed with waterand saturated saline solution, and dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas recrystallized from ethyl acetate to give 32 mg (44%) of the titlecompound.

Example 182 tert-Butyl1-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinylcarbamate

The title compound 176 mg (58%) was obtained in a manner similar to theExample 166 by use of tert-butyl 4-piperidinecarbamate, instead ofN-methylpiperazine.

Example 183 tert-Butyl 1(cis-4-{[(1-cyclohexyl-3-dimethyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinylcarbamate

The title compound 94 mg (31%) was obtained as by-product in the Example182.

Example 184N-[trans-4-(4-Amino-1-piperidinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 82 mg (60%) was obtained in a manner similar to theExample 165 by use of the compound obtained in the Example 182, insteadof the compound obtained in the Example 164.

Example 185N-[cis-4-(4-Amino-1-piperidinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 63 mg (95%) was obtained in a manner similar to theExample 165 by use of the compound obtained in the Example 183, insteadof the compound obtained in the Example 164.

Example 186 tert-Butyl4-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate

The title compound 218 mg (74%) was obtained in a manner similar to theExample 166 by use of tert-butyl 1-piperazinecarboxylate, instead ofN-methylpiperazine.

Example 187 tert-Butyl4-(cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate

The title compound 72 mg (14%) was obtained as by-product in the Example186.

Example 1881-Cyclohexyl-3-methyl-N-[trans-4-(1-piperazinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 146 mg (86%) was obtained in a manner similar to theExample 165 by use of the compound obtained in the Example 186, insteadof the compound obtained in the Example 164.

Example 1891-Cyclohexyl-3-methyl-N-[cis-4-(1-piperazinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 51 mg (97%) was obtained in a manner similar to theExample 165 by use of the compound obtained in the Example 187, insteadof the compound obtained in the Example 164.

Example 190N-[trans-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 81 mg (95%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example188, instead of the compound obtained in the Manufacturing Example 2.

Example 1911-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1,4-diazepam-1-yl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamidehemifumarate

To a solution of 143 mg (0.305 mmol) of the compound obtained in theExample 144 in 2 mL of ethanol was added 38.9 mg (0.335 mmol) of fumaricacid, and the resulting precipitates were collected to give 139 mg (86%)of the title compound.

Example 192 5-Methyl-2-tetrahydro-2H-pyran4-yl-2,4-dihydro-3H-pyrazole-3-one

The title compound 6.93 g (58%) was obtained in a manner similar to theExample 1 by use of 4-tetrahydropyranylhydrazine, instead ofcyclohexylhydrazine HCl salt.

Example 1935-Chloro-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-pyrazole-4-carboxaldehyde

A mixture solution of 6.87 g (3.77 mmol) of the compound obtained in theExample 192 and 14.1 mL (150.8 mmol) of phosphorous oxychloride wasstirred for 1 hour at 110° C. After the reaction mixture was cooled toroom temperature, this mixture was added gradually to ice-cooled 40 mLof N,N-dimethylformamide, and the mixture was stirred for 1 hour at roomtemperature and for 3 hours at 90° C. Then, the react ion mixture wascooled with ice and diluted with ethyl acetate, and pH of the reactionmixture was adjusted to 4 by adding 2N—NaOH aqueous solution. Themixture was extracted with ethyl acetate and the organic layer waswashed with saturated saline solution and then, dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified by silica gel column chromatography(eluent: hexane/ethyl acetate=2/1) to give 4.64 g (54%) of the titlecompound.

Example 194 Ethyl3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxylate

To a solution of 16.54 mL (0.151 mol) of ethyl thioglycolate in 300 mLof tetrahydrofuran was added 6.03 g (0.151 mol) of sodium hydride (60%oily) in small portions, and the mixture was stirred for 3 minutes.Then, 31.36 g (0.137 mol) of the compound obtained in the Example 193was added to this mixture at once, and the mixture was stirred for 1hour. Further, 6.03 g (0.151 mol) of sodium hydride (60% oily) was addedto this mixture in small portions at 0° C., and the mixture was stirredfor 1 hour. The reaction mixture was diluted with ethyl acetate and theorganic layer was washed with water and saturated saline solution, anddried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=3/1 to 2/1) to give 30.1 g(76%) of the title compound.

Example 1953-Methyl-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxylicacid

The title compound 4.26 g (99%) was obtained in a manner similar to theExample 6 by use of the compound obtained in the Example 194, instead ofthe compound obtained in the Example 5.

Example 1963-Methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 166 mg (84%) was obtained in a manner similar to theExample 7 by use of 4-(4-methyl-1-piperazinyl)aniline and the compoundobtained in Example 194, instead of benzylamine and the compoundobtained in the Example 6, respectively.

Example 197N-[3-Fluoro-4-(4-methyl-piperazinyl)phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 214 mg (83%) was obtained in a manner similar to theExample 7 by use of [3-fluoro-4-(4-methyl-1-piperazinyl)]aniline and thecompound obtained in Example 195, instead of benzylamine and thecompound obtained in the Example 6, respectively.

Example 1981-Cyclohexyl-3-methyl-N-[4-(4-morpholinylmethyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 173 mg (87%) was obtained in a manner similar to theExample 7 by use of 4-(4-morpholinylmethyl)aniline, instead ofbenzylamine.

Example 1991-Cyclohexyl-3-methyl-N-[4-(4-morpholinylmethyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamidefumarate

41.7 mg (0.59 mmol) of fumaric acid was added to a mixture of 150 mg(0.432 mmol) of the compound obtained in the Example 198 in 1 mL ofethanol, and 2 mL of diethyl ether was further added to the mixture.Then, the mixture was stirred for over night and appeared precipitateswere collected by filtration to give 112 mg (59%) of the title compound.

Example 2001-Cyclohexyl-N-{4-[(dimethylamino)ethyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 83 mg (75%) was obtained in a manner similar to theExample 7 by use of 4-[(2-dimethylamino)ethyl]aniline, instead ofbenzylamine.

Example 2011-Cyclohexyl-3-methyl-N-{4-[2-(4-morpholinyl)ethyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 140 mg (68%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Example 32, instead ofbenzylamine.

Example 2021-Cyclohexyl-methyl-N-{4-[(3-methyl-2,5-dioxo-1-imidazolidinyl)-methyl]phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 185 mg (88%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Example 34, instead ofbenzylamine.

Example 2031-Cyclohexyl-3-methyl-N-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)-phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 116 mg (57%) was obtained in a manner similar to theExample 7 by use of 4-(3-methyl-2,5-dioxo-1-imidazolidinyl)aniline,instead of benzylamine.

Example 204 Methyltrans-4-{[(1-cyclohex-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound 2.18 g (95%) was obtained in a manner similar to theExample 7 by use of methyl trans-4-aminocyclohexanecarboxylate, insteadof benzylamine.

Example 2054-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}cyclohexanecarboxylic acid

The title compound 1.48 g (quantitative) was obtained in a mannersimilar to the Example 41 by use of the compound obtained in the Example204, instead of the compound obtained in the Example 40.

Example 2061-Cyclohexyl-N-[4-(hydroxymethyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 200 mg (0.496 mmol) of the compound obtained in theExample 204 in 5 mL of tetrahydrofuran was added 43 mg (1.98 mmol) oflithium borohydride, and the mixture was stirred for 1.5 hours underheating at 70° C. The reaction mixture was cooled to room temperatureand water was added to the mixture and mixture was extracted withdichloromethane. The organic layer was dried over with anhydrous sodiumsulfate and the solvent was removed under reduced pressure. Theresulting residue was recrystallized from isopropanol/hexane (1/1) togive 76 mg (41%) of the title compound.

Example 2071-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]-cyclohexyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 200 mg (0.513 mmol) of the compound obtained in theExample 205 in 5 mL of dichloromethane and 1 mL of N,N-dimethylformamidewere added 51.3 μL (0.462 mmol) of N-methylpiperazine and 750 mg of PScarbodiimide (Argonaut Co.), and the mixture was stirred for over nightat room temperature. The reagent removed off by filtration and thefiltrate was condensed to give 36 mg (15%) of the title compound.

Example 2081-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 18 mg (8%) was obtained in a manner similar to theExample 207 by use of 2M-dimethylamine in tetrahydrofuran, instead ofN-methylpiperazine.

Example 209N-(4-Cyanocyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide

The title compound 189 mg (84%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Example 36, instead ofbenzylamine.

Example 210 tert-Butyl2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}ethyl(ethyl)carbamate

The title compound 1.89 g (99%) was obtained in a manner similar to theExample 7 by use of [2-(N-Boc-N-methyl)amino]ethylamine, instead ofbenzylamine.

Example 2111-Cyclohexyl-3-methyl-N-[2-(methylamino)ethyl]-1H-thieno[2,3-c]-pyrazole-5-carboxamide2HCl salt

The title compound 1.71 g (quantitative) was obtained in a mannersimilar to the Manufacturing Example 4 by use of the compound obtainedin the Example 210, instead of the compound obtained in theManufacturing Example 3.

Example 212N-{2-[Acetyl(methyl)amino]ethyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5carboxamide

To a solution of 150 mg (0.381 mmol) of the compound obtained in theExample 211 in 5 mL of dichloromethane were added 54 μL (0.572 mmol) ofacetic anhydride and 123 μL (1.53 mmol) of pyridine, and the mixture wasstirred for 1 hour at room temperature. Then, 54 μL (0.5721 mmol) ofacetic anhydride and 123 μL (1.53 mmol) of pyridine were further addedto the reaction mixture, and the mixture was stirred for 1 hour at roomtemperature. Water was added to the reaction mixture and the mixture wasextracted with dichloromethane, and the organic layer was dried overwith anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=30/1) to give 120 mg(87%) of the title compound.

Example 2131-Cyclohexyl-3-methyl-N-{2-[methyl(methylsulfonyl)amino]ethyl}-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

To a solution of 150 mg (0.381 mmol) of the compound obtained in theExample 211 in 5 nm of dichloromethane were added 44 μL (0.572 mmol) ofmethanesulfonyl chloride and 212 μL (1.53 mmol) of triethylamine, andthe mixture was stirred for 1 hour at room temperature. After thereaction, water was added to the reaction mixture and the mixture wasextracted with dichloromethane. The organic layer was dried over withanhydrous sodium sulfate and the solvent was removed under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=40/1), and the eluatewas treated with 4N—HCl/dioxane to give 128 mg (77%) of the titlecompound.

Example 214 Ethyl(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-piperidinyl)acetate

To a solution of 250 mg (0.722 mol) of the compound obtained in theExample 134 in 6 mL of dichloromethane were added 88 μL (0.794 mmol) ofethyl bromoacetate and 151 μL (1.082 mmol) of triethylamine, and themixture was stirred for 3 days at room temperature. Then, water wasadded to the reaction mixture and the mixture was extracted withdichloromethane. The organic layer was dried over with anhydrous sodiumsulfate and the solvent was removed under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/1) to give 237 mg (76%) of thetitle compound.

Example 215(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-1-piperidinyl)aceticacid

The title compound 176 mg (86%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 214, insteadof the compound obtained in the Example 40.

Example 216 Ethyl2-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-piperidinyl)-2-methylpropanoate

To a solution of 252 mg (0.727 mmol) of the compound obtained in theExample 134 in 5 mL of N,N-dimethylformamide were added 128 μL (0.873mmol) of ethyl 2-bromoisobutyrate and 152 μL (1.09 mmol) oftriethylamine, and the mixture was stirred for over night at 70° C.Then, water was added to the reaction mixture and the mixture wasextracted with dichloromethane. The organic layer was dried over withanhydrous sodium sulfate and the solvent was removed under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=40/1) to give 115 mg(34%) of the title compound.

Example 2172-(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-piperidinyl-2-methylpropanoicacid

The title compound 65 mg (69%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 216, insteadof the compound obtained in the Example 40.

Example 218N-[4-(4-Hydroxy-1-piperidinyl)phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 198 mg (90%) was obtained in a manner similar to theExample 7 by use of 1-(4-aminophenyl)-4-piperidinol and the compoundobtained in the Example 195, instead of benzylamine and the compoundobtained in the Example 6, respectively.

Example 2191-Cyclohexyl-N-[2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)-ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.488 mol) of the compound obtained in theExample 122 in 5 mL of tetrahydrofuran were added 75.6 mg (0.586 mmol)of 5,5-dimethyloxazolidine-dione, 154 mg (0.586 mmol) oftriphenylphosphine and 267 μL (0.586 mmol) of diethyl azodicarboxylate(40% toluene solution), and the mixture was stirred for 2 hours at roomtemperature. After the reaction, water was added to the reaction mixtureand the mixture was extracted with dichloromethane. The organic layerwas dried over with anhydrous sodium sulfate and the solvent was removedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: dichloromethane/acetone=2/1 for firsttrial, and hexane/ethyl acetate=2/1 for second trial) to give 133 mg(65%) of the title compound.

Example 220 1-Cyclohexyl-3-methyl-N-{[methyl(4-morpholinylcarbonyl)amino]ethyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 164 mg (99%) was obtained in a manner similar to theExample 214 by use of the compound obtained in the Example 211 and4-morpholinylcarbonyl chloride, instead of the compound obtained in theExample 134 and ethyl bromoacetate, respectively.

Example 2211-Cyclohexyl-N-{2-[(dimethylamino)carbonyl)(methyl)amino]ethyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 119 mg (80%) was obtained in a manner similar to theExample 214 by use of the compound obtained in the Example 211 anddimethylaminocarbonyl chloride, instead of the compound obtained in theExample 134 and ethyl bromoacetate, respectively.

Example 222 Methyl2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}ethyl(methyl)carbamate

To a solution of 150 mg (0.381 mmol) of the compound obtained in theExample 211 in 5 mL of dichloromethane and 5 mL of water were added 158mg (1.14 mmol) of potassium carbonate and 44 μL (0.572 mmol) of ethylchlorocarbonate, and the mixture was stirred for over night at roomtemperature. Then, water was added to the reaction mixture and themixture was extracted with dichloromethane. The organic layer was driedover with anhydrous sodium sulfate and the solvent was removed underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: dichloromethane/methanol=40/1) to give120 mg (83%) of the title compound.

Example 2231-Cyclohexyl-N-{2-[(methoxyacetyl)(methyl)amino]ethyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 124 mg (83%) was obtained in a manner similar to theExample 214 by use of the compound obtained in the Example 211 andmethoxyacetyl chloride, instead of the compound obtained in the Example134 and ethyl bromoacetate, respectively.

Example 2241-Cyclohexyl-N-{2-[glycoloyl(methyl)amino]ethyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.3811 mmol) of the compound obtained in theExample 211 in 6 mL of dichloromethane were added 34.8 mg (0.458 mmol)of hydroxyacetic acid, 186 μL (1.335 mmol) of triethylamine, 61.8 mg(0.458 mmol) of N-hydroxybenzotriazole and 80.4 mg (0.419 mmol) of1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide, and the mixture wasstirred for 3 hours at room temperature. Then, water was added to thereaction mixture and the mixture was extracted with dichloromethane. Theorganic layer was dried over with anhydrous sodium sulfate and thesolvent was removed under reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 87 mg (60%) of the titlecompound.

Example 2251-Cyclohexyl-N-(4-{[(2-hydroxyethyl)(methyl)amino]carbonyl}-cyclohexyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 128 mg (74%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 205 and2-N-methylaminoethanol, instead of the compound obtained in the Example211 and hydroxyacetic acid, respectively.

Example 226 Methyl(1S,3S)-3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclopentanecarboxylate

The title compound 565 mg (97%) was obtained in a manner similar to theExample 7 by use of methyl (1S,3S)-3-aminocyclopentanecarboxylate,instead of benzylamine.

Example 227(1S,3S)-3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclopentanecarboxylicacid

The title compound 542 mg (quantitative) was obtained in a mannersimilar to the Example 41 by use of the compound obtained in the Example226, instead of the compound obtained in the Example 40.

Example 2281-Cyclohexyl-3-methyl-N-[2-(4-methyl-2,3-dioxo-1-piperazinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 88 mg (35%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Example 37, instead ofbenzylamine.

Example 2291-Cyclohexyl-N-{(1S,3S)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 176 mg (91%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 227 and2M-dimethylamine tetrahydrofuran solution, instead of the compoundobtained in the Example 211 and hydroxyacetic acid, respectively.

Example 2301-Cyclohexyl-N-{(1S,3S)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

The title compound 137 mg (84%) was obtained in a manner similar to theExample 125 by using the compound obtained in the Example 229, insteadof the compound obtained in the Example 124.

Example 231 Methyl(1R,3R)-3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclopentanecarboxlate

The title compound 772 mg (99%) was obtained in a manner similar to theExample 7 by use of methyl (1R,3R)-3-aminocyclopentanecarboxylate,instead of benzylamine.

Example 232(1R,3R)-3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclopentanecarboxylicacid

The title compound 822 mg (quantitative) was obtained in a mannersimilar to the Example 41 by use of the compound obtained in the Example231, instead of the compound obtained in the Example 40.

Example 2331-Cyclohexyl-N-{(1R,3R)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 153 mg (79%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 232 and2M-dimethylamine tetrahydrofuran solution, instead of the compoundobtained in the Example 211 and hydroxyacetic acid, respectively.

Example 234 1-CyclohexylN-{(1R,3R)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

The title compound 80 mg (54%) was obtained in a manner similar to theExample 125 by use of the compound obtained in the Example 233, insteadof the compound obtained in the Example 124.

Example 2351-Cyclohexyl-N-{1-[(dimethylamino)carbonyl]-4-piperidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 241 mg (95%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example39, instead of benzylamine.

Example 2361-Cyclohexyl-3-methyl-N-[4-(4-morpholinylcarbonyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 236 mg (96%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 205 andmorpholine, instead of the compound obtained in the Example 211 andhydroxyacetic acid, respectively.

Example 2371-Cyclohexyl-3-methyl-N-{4-[(methylamino)carbonyl]cyclohexyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 122 mg (79%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 205 andmethylamine (30% ethanol solution), instead of the compound obtained inthe Example 211 and hydroxyacetic acid, respectively.

Example 2381-Cyclohexyl-N-{4-[(cyclopropylamino)carbonyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

The title compound 115 mg (64%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 205 andcyclopropylamine, instead of the compound obtained in the Example 211and hydroxyacetic acid, respectively.

Example 2391-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)carbonyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 157 mg (86%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 205 and4-hydroxypiperidine, instead of the compound obtained in the Example 211and hydroxyacetic acid, respectively.

Example 2401-Cyclohexyl-N-{1-[(dimethylamino)sulfonyl]-4-piperidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 257 mg (99%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example41, instead of benzylamine.

Example 241 tert-Butyl4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-1-piperidinecarboxylate

The title compound 2.57 g (98%) was obtained in a manner similar to theExample 7 by use of 4-amino-1-Boc-piperidine, instead of benzylamine.

Example 2421-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamidedi-HCl salt

The title compound 2.29 g (97%) was obtained in a manner similar to theManufacturing Example 4 by using the compound obtained in the Example241, instead of the compound obtained in the Manufacturing Example 3.

Example 243N-[(3S)-1-Benzylpyrrolidinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 2.32 g (97%) was obtained in a manner similar to theExample 7 by use of (3S)-1-benzyl-3-aminopyrrolidine, instead ofbenzylamine.

Example 2441-Cyclohexyl-3-methyl-N-[(3S)-pyrrolidinyl]-1H-thieno[2,3-c]-pyrazole-5-carboxamide

To a solution of 2.26 g (5.35 mmol) of the compound obtained in theExample 243 in 50 mL of 1,2-dichloroethane was added 721 μL (6.68 mmol)of 1-chloroethyl chloroformate, and the mixture was refluxed for 2hours. Then, 289 μL (2.67 mmol) of 1-chloroethyl chloroformate wasfurther added to this mixture and the mixture was refluxed for 1 hourunder stirring. The solvent was removed under reduced pressure and 50 mLof methanol was added to the residue, and the mixture was refluxed for30 minutes. The solvent was removed under reduced pressure and theresidue was treated with saturated sodium bicarbonate aqueous solution,and the mixture was extracted with dichloromethane. The organic layerwas dried over with anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (eluent: dichloromethane/methanol=20/1) to give0.83 g (47%) of the title compound.

Example 2451-Cyclohexyl-N-{(3S)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 155 mg (85%) was obtained in a manner similar to theExample 214 by use of the compound obtained in the Example 244 anddimethylaminocarbonyl chloride, instead of the compound obtained in theExample 134 and ethyl bromoacetate, respectively.

Example 2461-Cyclohexyl-N-{(3S)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

The title compound 155 mg (85%) was obtained in a manner similar to theExample 125 by use of the compound obtained in the Example 245, insteadof the compound obtained in the Example 124.

Example 2471-Cyclohexyl-N-{4-[(2,5-dioxo-1-imidazolidinyl)methyl]cyclohexyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 136 mg (0.362 mmol) of the compound obtained in theExample 206 in 10 mL of tetrahydrofuran were added 72 mg (0.724 mmol) ofhydantoin, 135 μL (0.543 mmol) of tri-n-butylphosphine and1,1′-azobis(N,N-dimethylformamide), and the mixture was stirred for 3hours at 60° C. The reaction mixture was cooled to room temperature,treated with water, and extracted with ethyl acetate. The organic layerwas dried over with anhydrous sodium sulfate and removed under reducedpressure. The residue was purified by silica gel column chromatography(eluent: ethyl acetate) to give 96 mg (58%) of the title compound.

Example 248 Ethyl1-[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-4-piperidinecarboxylate

The title compound 2.73 g (98%) was obtained in a manner similar to theExample 7 by using ethyl isonipecotic acid, instead of benzylamine.

Example 2491-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-1-yl)carbonyl]-4-piperidinecarboxylicacid

The title compound 1.1 g (99%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 248, insteadof the compound obtained in the Example 40.

Example 2501-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-N-methyl-4-piperidinecarboxamide

The title compound 195 mg (94%) was obtained in a manner similar to theExample 224 by use of methylamine (30% ethanol solution) and thecompound obtained in the Example 249, instead of the compound obtainedin the Example 211 and hydroxyacetic acid, respectively.

Example 251 Ethyl(3S)-1-[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-3-piperidinecarboxylate

The title compound 2.29 g (quantitative) was obtained in a mannersimilar to the Example 7 by use of ethyl (R)-nipecotic acid, instead ofbenzylamine.

Example 252N-[(6S,7aS)-1,3-Dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 595 mg (74%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example45, instead of benzylamine.

Example 253N-[(6S,7aS)-2-Methyl-1,3-dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5carboxamide HCl salt

To a solution of 150 mg (0.374 mmol) of the compound obtained in theExample 252 in 10 mL of tetrahydrofuran were added 30 μL (0.747 mmol) ofmethanol, 122 mg (0.476 mmol) of triphenylphosphine and 213 μL (0.467mmol) of diethylazodicarboxylate (40% toluene solution), and the mixturewas stirred for 1 hour at room temperature. Then, the solvent wasremoved under reduced pressure and the residue was purified by silicagel column chromatography (eluent: hexane/acetone=2/1 for first trial;dichloromethane/ethyl acetate=1/1 for second trial), and obtainedproduct was converted to the HCl salt by treating with 100 μL of4N—HCl/dioxane solution and recrystallized from methanol-ethanol (1/1)to give 23 mg (15%) of the title compound.

Example 254(±)-{1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-3-piperidinyl}methanol

The title compound 595 mg (74%) was obtained in a manner similar to theExample 7 by use of (±)-3-hydroxymethylpiperidine, instead ofbenzylamine.

Example 255 N-{4-[(Dimethylamino)carbonyl]phenyl}-3-methyl-1tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 123 mg (80%) was obtained in a manner similar to theExample 7 by use of 4-(dimethylaminocarbonyl)aniline, instead ofbenzylamine.

Example 2561-Cyclohexyl-3-methyl-N-[6-(2-oxo-1-imidazolidinyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 199 mg (83%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example46, instead of benzylamine.

Example 2571-Cyclohexyl-N-[(1S,3S)-3-(hydroxymethyl)cyclopentyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 462 mg (quantitative) was obtained in a mannersimilar to the Example 206 by use of the compound obtained in theExample 226, instead of the compound obtained in the Example 204.

Example 2581-Cyclohexyl-N-{(1S,3S)-3-[(2,5-dioxo-1-imidazolidinyl)methyl]cyclopentyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 74 mg (40%) was obtained in a manner similar to theExample 247 by use of the compound obtained in the Example 257, insteadof the compound obtained in the Example 206.

Example 2591-Cyclohexyl-N-[4-(2,5-dioxo-1-imidazolidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 54 mg (27%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example47, instead of benzylamine.

Example 260 3-MethylN-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 104 mg (61%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example48 and the compound obtained in the Example 195, instead of benzylamineand the compound obtained in the Example 6, respectively.

Example 261 3-Methyl-N-[6-(2-oxo-1-imidazolidinyl)-3-piperidinyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 101 mg (63%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example46 and the compound obtained in the Example 195, instead of benzylamineand the compound obtained in the Example 6, respectively.

Example 2621-Cyclohexyl-N-{4-[(3R)-3-hydroxypyrrolidinyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 308 mg (64%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example49, instead of benzylamine.

Example 2631-Cyclohexyl-N-{3-fluoro-4-[(3R)-3-hydroxypyrrolidinyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 397 mg (79%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example51, instead of benzylamine.

Example 2641-Cyclohexyl-N-{3-[(4-hydroxy-1-piperidinyl)sulfonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 80 mg (35%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example53, instead of benzylamine.

Example 265N-{4-[4-{[tert-Butyl(dimethyl)silyl]oxy}-1-piperidinyl]sulfonyl}-phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-]pyrazole-5-carboxamide

The title compound 243 mg (69%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example56, instead of benzylamine.

Example 2661-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)sulfonyl]phenyl}-3-ethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 231 mg (0.374 mmol) of the compound obtained in theExample 265 in 5 mL of tetrahydrofuran was added 562 μL (0.562 mmol) oftetrabutylammoniumfluoride (1M-tetrahydrofuran solution), and themixture was stirred for over night at room temperature. Then, thereaction mixture was treated with ethyl acetate, and the organic layerwas washed with water, saturated saline solution and then, dried overwith anhydrous sodium sulfate. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=1/2) to give 176 mg (94%)of the title compound.

Example 2671-Cyclohexyl-N-[4-(2-hydroxyethyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 139 mg (64%) was obtained in a manner similar to theExample 7 by use of 4-aminophenethyl alcohol, instead of benzylamine.

Example 268N-[3-Fluoro-4-(4-hydroxy-piperidinyl)phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 161 mg (96%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example62 and the compound obtained in the Example 195, instead of benzylamineand the compound obtained in the Example 6, respectively.

Example 2691-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 229 mg (80%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example58, instead of benzylamine.

Example 2701-Cyclohexyl-3-methyl-N-[trans-4-(2-oxo-1,3-oxazolidin-3-yl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 150 mg (0.416 mmol) of the compound obtained in theExample 132 in 2.5 mL of tetrahydrofuran were added 52 μL (0.50 mmol) of2-chloroethyl chloroformate and 87 μL (0.624 mmol) of triethylamine, andthe mixture was stirred for 3 hours at room temperature. Saturatedsodium bicarbonate aqueous solution was added to the reaction mixtureand the mixture was extracted with chloroform. The organic layer waswashed with water and saturated saline solution and dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureto give urethane intermediate compound.

Next, to a mixture solution of the urethane intermediate compoundobtained above in 2 mL of ethanol and 4 mL of tetrahydrofuran was added2 mL of 4M-NaOH aqueous solution, and the mixture was stirred for 40hours at room temperature. The solvent was removed under reducedpressure and the residue was treated with water, and the mixture wasextracted with chloroform. The organic layer was washed with water andsaturated saline solution and dried over with anhydrous sodium sulfate.The solvent was removed under reduced pressure and the residue waspurified by silica gel column chromatography (eluent:chloroform/methanol=10/1) to give 180 mg (quantitative) of the titlecompound.

Example 2711-Cyclohexyl-3-methyl-N-[trans-4-(2-oxo-1-imidazolidinyl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 150 mg (0.416 mmol) of the compound obtained in theExample 132 in 4 mL of tetrahydrofuran was added 71 μL (0.832 mmol) of2-chloroethylisocyanate, and the mixture was stirred for 3.5 hours atroom temperature. 2 mL of 1M-NaOH aqueous solution was added to thereaction mixture, and the mixture was stirred. Then, further 5 mL of4M-NaOH aqueous solution and 15 mL of tetrahydrofuran were added to themixture, and the mixture was stirred for 2 hours. Next, 5 μL of15-crown-5 was added to the reaction mixture and the mixture was furtherstirred for 43 hours at room temperature, then, 5 mL of ethanol wasadded to the reaction mixture and stirred for 6 hours at 80° C. Thesolvent was removed under reduced pressure and the residue was treatedwith water. The mixture was extracted with chloroform and the organiclayer was washed with water and saturated saline solution, then, driedover with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: chloroform/methanol=10/1) to give 106 mg (55%)of the title compound.

Example 2724-[(trans-4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclohexyl)amino]-4-oxobutanoicacid

To a suspension of 150 mg (0.416 mmol) of the compound obtained in theExample 132 in 5 mL of xylene was added 62 mg (0.624 mmol) of succinicanhydride, and the mixture was refluxed for 5 hours. The solvent wasremoved under reduced pressure and the residue was treated with ether.The appeared precipitates were collected to give 178 mg (93%) of thetitle compound.

Example 2731-Cyclohexyl-N-[trans-4-(2,5-dioxo-1-pyrrolidinyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

A mixture of 141 mg (0.306 mol) of the compound obtained in the Example272, 2 mL of acetic anhydride and 33 mg of sodium acetate was stirredfor 3 hours at 60° C. and for 14 hours at 80° C., then, 2 mL of aceticanhydride was further added to the reaction mixture, and the mixture wasstirred for 6 hours at 100° C. After the reaction, ice water was addedto the reaction mixture and the mixture was neutralized by addingsaturates sodium bicarbonate aqueous solution, and extracted withchloroform. The organic layer was washed with water and saturated salinesolution, and dried over with anhydrous sodium sulfate. The solvent wasremoved under reduced pressure and the residue was treated with ethanolto give 59 mg (49%) of the title compound.

Example 2741-Cyclohexyl-N-[trans-(1,1-dioxide-2-isothiazolidinyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.416 mmol) of the compound obtained in theExample 132 in 10 mL of dichloromethane were added 87 μL (0.624 mmol) oftriethylamine and 61 μL (0.50 mmol) of 3-chloropropanesulfonyl chloride,and the mixture was stirred for 1.5 hours at room temperature. Water wasadded to the react ion mixture and the mixture was extracted withchloroform. The organic layer was washed with water and saturated salinesolution and dried over with anhydrous sodium sulfate. The solvent wasremoved under reduced pressure to give sulfonamide intermediatecompound.

Next, to a mixture solution of the sulfonamide intermediate compoundobtained above in 5 mL of ethanol was added 2 mL of 4M-NaOH aqueoussolution, and the mixture was stirred for 1.5 hours at room temperatureand for 3 hours at 80° C. The reaction mixture was cooled and treatedwith water, and then, extracted with chloroform. The organic layer waswashed with water and saturated saline solution and dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was recrystallized from ethanol to give 112 mg (58%) ofthe title compound.

Example 275 Benzyl [{[(trans-4-{[(1cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}(methyl)amino]acetate

To a solution of 200 mg (0.555 mmol) of the compound obtained in theExample 132 in 4 mL of tetrahydrofuran were added 66 mg (0.22 mmol) oftri-phosgene and 232 μL (1.66 mmol) of triethylamine, and the mixturewas stirred for 1 hour at room temperature. Then, 195 mg (0.55 mmol) ofp-toluene sulfonic acid sarcosine benzyl ester and 77 μL (0.555 mmol) oftriethylamine were added to the reaction mixture, and the mixture wasstirred for 5 hours at room temperature. Water was added to the reactionmixture and the mixture was extracted with chloroform, and the organiclayer was washed with water and saturated saline solution, then, driedover with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: chloroform/methanol=15/1) to give 227 mg (72%)of the title compound.

Example 2761-Cyclohexyl-3-methyl-N-[trans-4-(3-methyl-2,5-dioxo-1-imidazolidinyl)cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 207 mg (0.366 mmol) of the compound obtained in theExample 275 in 5 mL of ethanol was added 0.5 mL of 6M-HCl aqueoussolution and the mixture was refluxed for 4 hours. After the reaction,the mixture was neutralized by adding saturated sodium bicarbonateaqueous solution, and extracted with chloroform. The organic layer waswashed with water and saturated saline solution and dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified by silica gel column chromatography(eluent: chloroform/methanol=15/1) to give 169 g (quantitative) of thetitle compound.

Example 2771-Cyclohexyl-3-methyl-N-[2-(3-methyl-2,5-dioxo-1-imidazolidinyl)-ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.487 mmol) of the compound obtained in theExample 122 and 55.6 mg (0.487 mmol) of 1-methylhydantoin 4 mL oftetrahydrofuran were added 121 μL (0.487 mmol) of n-butylphosphine and83.8 mg (0.487 mmol) of 1,1′-azobis(N,N-dimethylformamide), and themixture was stirred for 5 hours at room temperature. The reactionmixture was treated with water and extracted with chloroform. Theorganic layer was washed with water and saturated saline solution, anddried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: ethyl acetate) to give 113 mg (58%) of the titlecompound.

Example 2781-Cyclohexyl-3-methyl-N-[3-(3-methyl-2,5-dioxo-1-imidazolidinyl)-propyl]-1H-thieno[2,3-c]pyrazole-5carboxamide

The title compound 147 mg (75%) was obtained in a manner similar to theExample 277 by use of the compound obtained in the Example 123, insteadof the compound obtained in the Example 122.

Example 2791-Cyclohexyl-N-[trans-[4-({[(2-hydroxyethyl)(methyl)amino]carbonyl}-aminocyclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 200 mg (0.555 mmol) of the compound obtained in theExample 132 in 4 mL of tetrahydrofuran were added 66 mg (0.22 mmol) oftriphosgene and 232 μL (1.66 mmol) of triethylamine and the mixture wasstirred for 1 hour at room temperature. Then, 54 μL (0.66 mmol) of2-(methylamino)ethanol was added to the reaction mixture and the mixturewas stirred for 3 hours at room temperature. The reaction mixture wastreated with water and extracted with chloroform, washed with water andsaturated saline solution, and then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent:chloroform/methanol=15/1) to give 190 mg (74%) of the title compound.

Example 2801-Cyclohexyl-3-methyl-N-[trans-[4-(3-methyl-2-oxo-1-imidazolidinyl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 187 mg (0.519 mmol) of the compound obtained in theExample 279 in 6 mL of tetrahydrofuran was added 140 mg (1.25 mmol) ofpotassium tert-butoxide and the mixture was cooled to 0° C. Then, asolution of 119 mg (0.623 mmol) of p-toluenesulfonyl chloride in 2 mL oftetrahydrofuran was added gradually to the reaction mixture and themixture was stirred for 30 minutes at room temperature. The reactionmixture was treated with water and extracted with chloroform. Theorganic layer was washed with water and saturated saline solution anddried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: chloroform/methanol=20/1) to give 115 mg (64%)of the title compound.

Example 281 Ethyl3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}propanoate

The title compound 716 mg (98%) was obtained in a manner similar to theExample 7 by use of β-alanine ethyl ester HCl salt, instead ofbenzylamine.

Example 282N-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-yl)carbonyl]-β-alanine

The title compound 620 mg (99%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 281, insteadof the compound obtained in the Example 40.

Example 283 tert-Butyl{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}acetate

The title compound 663 mg (88%) was obtained in a manner similar to theExample 7 by use of glycine tert-butyl ester HCl salt, instead ofbenzylamine.

Example 284{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}aceticacid

A mixture solution of 637 mg (1.68 mmol) of the compound obtained in theExample 283 and 5 mL of 4M-HCl/dioxane was stirred for 5 hours at roomtemperature, and after the reaction, the solvent was removed underreduced pressure. The residue was treated with water and extracted withchloroform, and the organic layer was washed with water and saturatedsaline solution, then, dried over with anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to give 556 mg (quantitative)of the title compound.

Example 2851-Cyclohexyl-3-methyl-N-[3-(4-morphonyl)-3-oxopropyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

A suspension solution of 85 mg (0.253 mmol) of the compound obtained inthe Example 282, 246 mg (0.337 mmol) of PS-carbodiimide (Argonaut Co.),and 39 mg (0.287 mmol) of 1-hydroxybenzotriazole in 4 mL ofdichloromethane was stirred for 10 minutes at room temperature. To thereaction mixture was added 20 μL (0.228 mmol) of morpholine, and themixture was stirred for 20 hours at room temperature. Then, 267 mg(0.861 mmol) of MP-carbonate (Argonaut Co.) was added to the reactionmixture and the mixture was stirred for 3 hours at room temperature. Thereaction mixture was filtrated and the filtrate was condensed underreduced pressure. The residue was recrystallized from ethylacetate/hexane to give 80 mg (78%) of the title compound.

Example 286 tert-Butyl2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}ethylcarbamate

The title compound 2.23 g (97%) was obtained in a manner similar to theExample 7 by use of N-(2-aminomethyl)carbamic acid tert-butyl eater,instead of benzylamine.

Example 287N-(2-Aminoethyl)-1-cyclohexyl-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 2.18 g (5.36 mmol) of the compound obtained in theExample 286 in 20 mL of dichloromethane was added 5 mL of4M-HCl/dioxane, and the mixture was stirred for 18 hours at roomtemperature. After reaction, the solvent was removed under reducedpressure and the residue was neutralized with saturated sodiumbicarbonate aqueous solution, and extracted with chloroform. The organiclayer was washed with water and saturated saline solution, then, driedover with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was treated with ethanol to give 670 mg(41%) of the title compound.

Example 2881-Cyclohexyl-N-[3-(dimethylamino)-3-oxopropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 52 mg (57%) was obtained in a manner similar to theExample 285 by use of 2.0M-dimethylamine/tetrahydrofuran, instead ofmorpholine.

Example 2891-Cyclohexyl-3-methyl-N-{3-[methyl-(1-methyl-4-piperidinyl)amino]-3-oxopropyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 79 mg (70%) was obtained in a manner similar to theExample 285 by use of 1-methyl-4-(methylamino)piperidine, instead ofmorpholine.

Example 2901-Cyclohexyl-N-[3-(4-hydroxy-1-piperidinyl)-3-oxopropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 74 mg (70%) was obtained in a manner similar to theExample 285 by use of 4-hydroxypiperidine, instead of morpholine.

Example 2911-Cyclohexyl-3-methyl-N-[2-(4-morpholinyl-2-oxoethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 62 mg (63%) was obtained in a manner similar to theExample 285 by use of the compound obtained in the Example 284, insteadof the compound obtained in the Example 282.

Example 2921-Cyclohexyl-N-[2-(dimethylamino)-2-oxoethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 63 mg (71%) was obtained in a manner similar to theExample 285 by use of the compound obtained in the Example 284 and2.0M-dimethylamine/tetrahydrofuran, instead of the compound obtained inthe Example 282 and morpholine, respectively.

Example 2931-Cyclohexyl-3-methyl-N-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 68 mg (67%) was obtained in a manner similar to theExample 285 by use of the compound obtained in the Example 284 andN-methylpiperazine, instead of the compound obtained in the Example 282and morpholine, respectively.

Example 2941-Cyclohexyl-N-[2-(4-hydroxy-1-piperidinyl)-2-oxoethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 75 mg (73%) was obtained in a manner similar to theExample 285 by use of the compound obtained in the Example 284 and4-hydroxypiperidine, instead of the compound obtained in the Example 282and morpholine, respectively.

Example 2951-Cyclohexyl-3-methyl-N-[3-(4-methyl-1-piperazinyl)-3-oxopropyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 84 mg (80%) was obtained in a manner similar to theExample 285 by use of N-methylpiperazine, instead of morpholine.

Example 2961-cyclohexyl-3-methyl-N-{3-[4-methyl-1-piperidinyl]-3-oxopropyl}-1H-thieno[2,3-c]pyrazole-5-carboxamidefumarate

The title compound 41 mg (41%) was obtained in a manner similar to theExample 1.91 by use of the compound obtained in the Example 295, insteadof the compound obtained in the Example 144.

Example 2971-Cyclohexyl-3-methyl-N-{2-[methyl(1-methyl-4-piperidinyl)amino]-2-oxoethyl}-1-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 81 mg (74%) was obtained in a manner similar to theExample 285 by use of the compound obtained in the Example 284 and1-methyl-4-(methylamino)piperidine, instead of the compound obtained inthe Example 282 and morpholine, respectively.

Example 2981-Cyclohexyl-3-methyl-N-{2-[methyl(1-methyl-4-piperidinyl)amino-2-oxoethyl}-1H-thieno[2,3-c]pyrazole-5-carboxamidefumarate

The title compound 74 mg (79%) was obtained in a manner similar to theExample 191 by use of the compound obtained in the Example 297, insteadof the compound obtained in the Example 144.

Example 2991-Cyclohexyl-3-methyl-N-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 150 mg (0.490 mmol) of the compound obtained in theExample 287 in 3 mL of tetrahydrofuran were added 102 μL (0.735 mmol) oftriethylamine and 61 μL (0.590 mmol) of 2-chloroethyl chloroformate, andthe mixture was stirred for 2 hours at room temperature. Then, 210 mg(1.08 mmol) of 28%-sodium methoxide/methanol solution was added to thereaction mixture and the mixture was stirred for 2 hours at roomtemperature, and further 130 mg (0.674 mmol) of 28%-sodiummethoxide/methanol solution was added to the reaction mixture and theresulting mixture was stirred for 15 hours at room temperature. Then,the reaction mixture was treated with water and extracted withchloroform. The organic layer was washed with water and saturated salinesolution, then, dried over with anhydrous sodium sulfate. The solventwas removed under reduced pressure and the residue was recrystallizedfrom ethyl acetate to give 107 mg (58%) of the title compound.

Example 3001-cyclohexyl-N-[2-(1,1-dioxide-2-isothiazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 125 mg (62%) was obtained in a manner similar to theExample 274 by use of the compound obtained in the Example 287, insteadof the compound obtained in the Example 132.

Example 3011-Cyclohexyl-N-[2-({[(2-hydroxyethyl)(methyl)amino]carbonyl}amino)-ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 160 mg (60%) was obtained in a manner similar to theExample 279 by use of the compound obtained in the Example 287, insteadof the compound obtained in the Example 132.

Example 3021-Cyclohexyl-3-methyl-N-[2-(3-methyl-2-oxo-imidazolidinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 110 mg (80%) was obtained in a manner similar to theExample 280 by use of the compound obtained in the Example 301, insteadof the compound obtained in the Example 279.

Example 303 Ethyl4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}butanoate

The title compound 763 mg (67%) was obtained in a manner similar to theExample 7 by use of ethyl 4-aminobutyrate HCl salt, instead ofbenzylamine.

Example 3044-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}butanoicacid

The title compound 690 mg (quantitative) was obtained in a mannersimilar to the Example 41 by use of the compound obtained in the Example303, instead of the compound obtained in the Example 40.

Example 3051-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 98 mg (67%) was obtained in a manner similar to theExample 7 by use of 3-(2-aminoethyl)-2,4-imidazolidinedione, instead ofbenzylamine.

Example 3061-Cyclohexyl-N-[4-(dimethylamino)-4-oxobutyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 101 mg (85%) was obtained in a mariner similar to theExample 285 by use of the compound obtained in the Example 304 and2.0M-dimethylamine/tetrahydrofuran solution, instead of the compoundobtained in the Example 282 and morpholine, respectively.

Example 3071-Cyclohexyl-3-methyl-N-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.487 mmol) of the compound obtained in theExample 122 in 5 mL of tetrahydrofuran were added 90 mg (0.634 mmol) of1,5,5-trimethylhydantoin, 166 mg (0.634 mol) of triphenylphosphine and289 μL (0.634 mmol) of 40%-diethyl azodicarboxylate/toluene solution,and the mixture was stirred for 30 minutes at room temperature. Afterthe reaction, the reaction mixture was treated with water and extractedwith dichloromethane. The organic layer was washed with water andsaturated saline solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent: hexane/ethylacetate=1/2) to give 146 mg (69%) of the title compound.

Example 3081-cyclohexyl-N-[2-(2,4-dioxo-1,3-thiazolidine-3-yl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 106 mg (53%) was obtained in a manner similar to theExample 307 by use of 2,4-thiazolidinedione, instead of1,5,5-trimethylhydantoin.

Example 3091-Cyclohexyl-N-[1-(hydroxymethyl)cyclopropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 766 mg (93%) was obtained in a manner similar to theExample 7 by use of (1-aminocyclopropyl)methanol, instead ofbenzylamine.

Example 3101-Cyclohexyl-3-methyl-N-{1-[(3-methyl-2,5-dioxo-1-imidazolidinyl)-methyl]cyclopropyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 111 mg (58%) was obtained in a manner similar to theExample 307 by use of the compound obtained in the Example 309 and1-methylhydantoin, instead of the compound obtained in the Example 122and 1,5,5-trimethylhydantoin, respectively.

Example 311 Methyl[(2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-yl)-carbonyl]amino}ethyl)amino]acetate

To a solution of 170 mg (0.555 mmol) of the compound obtained in theExample 287 in 5 mL of acetonitrile were added 52.5 μL (0.555 mmol) ofmethyl bromoacetate and 153 mg (1.11 mmol) of potassium carbonate, andthe mixture was refluxed for 3 hours. The reaction mixture was cooledand filtrated. The filtrate was treated with water and extracted withethyl acetate. The organic layer was washed with water and saturatedsaline solution, then, dried over with anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel column chromatography (eluent:dichloromethane/methanol=20/1 to 10/1) to give 93 mg (44%) of the titlecompound.

Example 312 Methyl[(aminocarbonyl)(2-{[(1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}ethyl)amino]acetate

To a solution of 78.8 mg (0.208 mmol) of the compound obtained in theExample 311 in 1.5 mL of dioxane and 1.5 mL of water were added 25.3 mg(0.312 mmol) of potassium cyanate and 36 μL of acetic acid, and themixture was stirred for 1.5 hours at room temperature. The reactionmixture was treated with water and extracted with ethyl acetate. Theorganic layer was washed with water and saturated saline solution, then,dried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: ethyl acetate/methanol=20/1 to 10/1) to give 73mg (84%) of the title compound.

Example 3131-Cyclohexyl-N-[2-(2,4-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 68 mg (0.161 mmol) of the compound obtained in theExample 312 in 6 mL of methanol was added 13 mg (60% oily; 0.323 mmol)of sodium hydride, and the mixture was stirred for 1.5 hour at roomtemperature. The solvent was removed and the residue was treated withwater and extracted with ethyl acetate. The organic layer was washedwith water and saturated saline solution, and then, dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was recrystallized from ethanol to give 20 mg (32%) ofthe title compound.

Example 3141-Cyclohexyl-N-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 195 mg (96%) was obtained in a manner similar to theExample 307 by use of 5,5-dimethylhydantoin, instead of1,5,5-trimethylhydantoin.

Example 3151-Cyclohexyl-3-methyl-N-[2-(5-methyl-1,1-dioxide-1,2,5-thiadiazolidin-2-yl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 227 mg (94%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example60, instead of benzylamine.

Example 3161-Cyclohexyl-N-[2-(3-ethyl-2,4-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 84 mg (65%) was obtained in a manner similar to theExample 307 by use of the compound obtained in the Example 313 andethanol, instead of 1,5,5-trimethylhydantoin and the compound obtainedin the Example 122, respectively.

Example 3171-Cyclohexyl-3-methyl-N-[2-(3-methyl-2,4-dioxo-1-imidazolidinyl)-ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 82 mg (66%) was obtained in a manner similar to theExample 307 by use of the compound obtained in the Example 313 andmethanol, instead of 1,5,5-trimethylhydantoin and the compound obtainedin the Example 122, respectively.

Example 3181-Cyclohexyl-N-[(1S)-2-hydroxy-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 170 mg (56%) was obtained in a manner similar to theExample 7 by use of (S)-(+)-2-amino-1-propanol, instead of benzylamine.

Example 3191-Cyclohexyl-N-[(1S)-2-(2,5-dioxo-1-imidazolidinyl)-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 46 mg (24%) was obtained in a manner similar to theExample 307 by use of the compound obtained in the Example 318 andhydantoin, instead of the compound obtained in the Example 122 and1,5,5-trimethylhydantoin, respectively.

Example 320N-[(3R)-1-Benzylpyrrolidinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 2.32 g (97%) was obtained in a manner similar to theExample 7 by use of (3R)-(−)-1-benzyl-3-aminopyrrolidine, instead ofbenzylamine.

Example 3211-Cyclohexyl-3-methyl-N-[(3R)-pyrrolidinyl]-1H-thieno[2,3-c]-pyrazole-5-carboxamide

To a solution of 2.28 g (5.40 mmol) of the compound obtained in theExample 320 in 15 mL of dichloromethane was added gradually 1.16 mL(10.8 mmol) of 1-chloroethyl formate at 0° C., and the mixture wasstirred for 1 hour at the same temperature and for 2 hours at roomtemperature. The solvent was removed under reduced pressure and 25 mL ofethanol was added to the residue, then, the mixture was refluxed for 2.5hours. After cooling, the solvent was removed under reduced pressure,and the residue was treated with 6M-HCl aqueous solution. Water layerwas washed with ether, and neutralized by 4M-NaOH aqueous solution, andextracted with dichloromethane. The organic layer was washed with waterand saturated saline solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by alkaline silica gel column chromatography (eluent:dichloromethane/methanol=50/1 to 30/1) to give 1.06 g (59%) of the titlecompound.

Example 3221-Cyclohexyl-N-{(3R)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.451 mmol) of the compound obtained in theExample 321 in 5 mL of dichloromethane were added 50 μL (0.541 mmol) ofN,N-dimethylcarbamoyl chloride and 94 μL of (0.677 mmol) oftriethylamine, and the mixture was stirred for 4 hours at roomtemperature. The reaction mixture was treated with saturated sodiumbicarbonate aqueous solution and extracted with dichloromethane. Theorganic layer was washed with water and saturated saline solution, then,dried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by alkaline silica gelcolumn chromatography (eluent: dichloromethane/methanol=30/1 to 10/1) togive 177 mg (97%) of the title compound.

Example 3231-Cyclohexyl-N-{(3R)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

0.11 mL (0.44 mmol) of 4M-HCl/ethyl acetate was added to a solution of150 mg (0.372 mmol) of the title compound in 1 mL of ethyl acetate, andthe mixture was treated with ether, then, stirred for 2 hours. Theprecipitates were collected to give 152 mg (93%) of the title compound.

Example 3241-Cyclohexyl-N-[(1R)-2-hydroxy-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 357 mg (98%) was obtained in a manner similar to theExample 7 by use of (R)-(−)-2-amino-1-propanol, instead of benzylamine.

Example 3251-Cyclohexyl-N-[(1R)-2-(2,5-dioxo-1-imidazolidinyl)-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 67 mg (18%) was obtained in a manner similar to theExample 307 by use of the compound obtained in the Example 324 andhydantoin, instead of the compound obtained in the Example 122 and1,5,5-trimethylhydantoin, respectively.

Example 3261-Cyclohexyl-N-[(2S)-2-hydroxypropyl]-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide

The title compound 343 mg (94%) was obtained in a manner similar to theExample 7 by use of (S)-(−)-1-amino-2-propanol, instead of benzylamine.

Example 3271-Cyclohexyl-N-[(2R)-2-(2,5-dioxo-1-imidazolidinyl)propyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 57 mg (15%) was obtained in a mariner similar to theExample 307 by use of the compound obtained in the Example 326 andhydantoin, instead of the compound obtained in the Example 122 and1,5,5-trimethylhydantoin, respectively.

Example 3281-Cyclohexyl-N-[(2R)-2-hydroxypropyl]-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carboxamide

The title compound 338 mg (93%) was obtained in a manner similar to theExample 7 by use of (R)-(+)-1-amino-2-propanol, instead of benzylamine.

Example 3291-Cyclohexyl-N-[(2S)-2-(2,5-dioxo-1-imidazolidinyl)propyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 42 mg (11%) was obtained in a manner similar to theExample 307 by use of the compound obtained in the Example 328 andhydantoin, instead of the compound obtained in the Example 122 and1,5,5-trimethylhydantoin, respectively.

Example 3301-Cyclohexyl-N-[(1R)-1-(hydroxymethyl)propyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 355 mg (94%) was obtained in a manner similar to theExample 7 by use of (R)-(−)-2-amino-1-butanol, instead of benzylamine.

Example 3311-Cyclohexyl-N-{(1R)-1-[(2,5-dioxo-1-imidazolidinyl)methyl]propyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 66 mg (18%) was obtained in a manner similar to theExample 307 by use of the compound obtained in the Example 330 andhydantoin, instead of the compound obtained in the Example 122 and1,5,5-trimethylhydantoin, respectively.

Example 3321-Cyclohexyl-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 392 mg (99%) was obtained in a manner similar to theExample 7 by use of D-valinol, instead of benzylamine.

Example 3331-Cyclohexyl-N-{(1R)-1-[(2,5-dioxo-1-imidazolidinyl)methyl]-2-methylpropyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 97 mg (22%) was obtained in a manner similar to theExample 307 by use of the compound obtained in the Example 332 andhydantoin, instead of the compound obtained in the Example 122 and1,5,5-trimethylhydantoin, respectively.

Example 334 tert-Butyl2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-2-methylpropylcarbamate

The title compound 493 mg (quantitative) was obtained in a mannersimilar to the Example 7 by use of tert-butyl2-amino-2-methylpropylcarbamate, instead of benzylamine.

Example 335N-(2-Amino-1,1-dimethylethyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

A mixture solution of 470 mg (1.088 mmol) of the compound obtained inthe Example 334 in 2 mL of 4M-HCl/dioxane was stirred for 3 hours atroom temperature. Then, the solvent was removed under reduced pressureand the residue was treated with ether and the resultant precipitateswere collected. The collected precipitates were dissolved in water andthe mixture was neutralized with saturated sodium bicarbonate aqueoussolution, and extracted with dichloromethane. The organic layer waswashed with water and saturated saline solution and dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureto give 344 mg (92%) of the title compound.

Example 3361-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)-1,1-dimethylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 304 mg (0.882 mmol) of the compound obtained in theExample 335 in 5 mL of ethanol was added gradually a solution of 114 mg(0.882 mmol) of ethyl isocyanatoacetate in 5 mL of ethanol, and themixture was stirred for 3 hours at room temperature. The solvent wasremoved under reduced pressure and the residue was dissolved in 5 mL ofethanol, then, 5 mL of 6M-HCl aqueous solution was added to the mixture.The mixture was refluxed for 3 hours, and the solvent was removed underreduced pressure. The residue was neutralized with saturated sodiumbicarbonate aqueous solution and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated salinesolution and then, dried over with anhydrous sodium sulfate. The solventwas removed under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: ethyl acetate) to give 336 mg(91%) of the title compound.

Example 3371-Cyclohexyl-N-[2-(2,5-dioxo-imidazolidinyl)-1,1-dimethylethyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamideHCl salt

The title compound 227 mg (70%) was obtained in a manner similar to theExample 323 by use of the compound obtained in the Example 336, insteadof the compound obtained in the Example 322.

Example 338N-(3-Amino-2,2-dimethylpropyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 162 mg (41%) was obtained in a manner similar to theExample 7 by use of 2,2-dimethyl-1,3-propanediamine, instead ofbenzylamine.

Example 3391-Cyclohexyl-N-[3-(2,5-dioxo-1-imidazolidinyl)-2,2-dimethylpropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 123 mg (72%) was obtained in a manner similar to theExample 336 by use of the compound obtained in the Example 338, insteadof the compound obtained in the Example 335.

Example 340(±)-1-Cyclohexyl-N-[trans-2-(hydroxymethyl)cyclopropyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 280 mg (42%) was obtained in a manner similar to theExample 7 by use of (±)-trans-(2-aminocyclopropyl)methanol, instead ofbenzylamine.

Example 3411-Cyclohexyl-3-methyl-N-[4-(3-oxo-1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 215 mg (87%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example66, instead of benzylamine.

Example 3423-Methyl-N-[4(3-oxo-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 152 mg (77%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example66 and the compound obtained in the Example 195, instead of benzylamineand the compound obtained in the Example 6, respectively.

Example 343 Methyl3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}benzoate

The title compound 1.78 g (95%) was obtained in a manner similar to theExample 7 by use of methyl m-aminobenzoate, instead of benzylamine.

Example 3443-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}benzoicacid

The title compound 1.67 g (quantitative) was obtained in a mannersimilar to the Example 41 by use of the compound obtained in the Example343, instead of the compound obtained in the Example 40.

Example 3451-Cyclohexyl-N-{3-[(dimethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 145 mg (90%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 344 and2M-dimethylamine/tetrahydrofuran solution, instead of the compoundobtained in the Example 211 and hydroxyacetic acid, respectively.

Example 3461-Cyclohexyl-3-methyl-N-[3-(4-morpholinylcarbonyl)phenyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 167 mg (94%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 344 andmorpholine, instead of the compound obtained in the Example 211 andhydroxyacetic acid, respectively.

Example 347 Methyltrans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound 605 mg (99%) was obtained in a manner similar to theExample 7 by use of methyl trans-4-aminocyclohexanecarboxylate HCl saltand the compound obtained in the Example 195, instead of benzylamine andthe compound obtained in the Example 6, respectively.

Example 348trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexanecarboxylicacid

The title compound 540 mg (98%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 347, insteadof the compound obtained in the Example 40.

Example 349N-{trans-4-[(Dimethylamino)carbonyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 117 mg (91. %) was obtained in a manner similar tothe Example 224 by use of the compound obtained in the Example 348 and2M-dimethylanime/tetrahydrofuran solution, instead of the compoundobtained in the Example 211 and hydroxyacetic acid, respectively.

Example 3503-Methyl-N-[trans-4-(4-morpholinylcarbonyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 132 mg (93%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 348 andmorpholine, instead of the compound obtained in the Example 211 andhydroxyacetic acid, respectively.

Example 351N-{trans-4-[(4-Hydroxy-1-piperidinyl)carbonyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 137 mg (94%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 348 and4-hydroxypiperidine, instead of the compound obtained in the Example 211and hydroxyacetic acid, respectively.

Example 3523-Methyl-N-{trans-4-[(4-methyl-1-piperazinyl)carbonyl]cyclohexyl}-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 97 mg (76%) was obtained in a manner similar to theExample 224 by use of the compound obtained in the Example 348 and1-methylpiperazine, instead of the compound obtained in the Example 211and hydroxyacetic acid, respectively.

Example 3531-Cyclohexyl-3-methyl-N-[3-(4-morpholinyl)propyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 199 mg (90%) was obtained in a manner similar to theExample 7 by use of N-(3-aminopropyl)morpholine, instead of benzylamine.

Example 3541-Cyclohexyl-3-methyl-N-[2-(4-morpholinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 174 mg (82%) was obtained in a manner similar to theExample 7 by use of N-(2-aminoethyl)morpholine, instead of benzylamine.

Example 3551-Cyclohexyl-3-methyl-N-[2-(1-piperidinyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 148 mg (70%) was obtained in a manner similar to theExample 7 by use of N-(2-aminoethyl)piperidine, instead of benzylamine.

Example 356N-[trans-4-(Hydroxymethyl)cyclohexyl]-3-ethyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 628 mg (96%) was obtained in a manner similar to theExample 206 by use of the compound obtained in the Example 347, insteadof the compound obtained in the Example 204.

Example 357(trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)methylp-toluenesulfonate

To a suspension solution of 510 mg (1.35 mmol) of the compound obtainedin the Example 356 in 20 mL of dichloromethane and 20 mL of chloroformwere added 270 mg (1.42 mmol) of p-toluenesulfonyl chloride and 131 μL(1.62 mmol) of pyridine, and the mixture was stirred for over night atroom temperature. Then, further 270 mg (1.42 mmol) of p-toluenesulfonylchloride and 131 μL (1.62 mmol) of pyridine were added twice to thereaction mixture at 50° C., and the mixture was stirred for over night.Further, 270 mg (1.42 mmol) of p-toluenesulfonyl chloride, 131 μL (1.62mmol) of pyridine and 226 μL (1.62 mmol) of triethylamine were addedtwice to the reaction mixture, and the mixture was stirred for overnight. Then, the reaction mixture was washed with water and dried overwith anhydrous sodium sulfate. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=1/1 to ethyl acetate only)to give 402 mg (56%) of the title compound.

Example 3583-Methyl-N-[trans-4-(4-morpholinylmethyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 120 mg (0.226 mmol) of the compound obtained in theExample 357 in 5 mL of N,N-dimethylformamide was added 79 μL (0.903mmol) of morpholine, and the mixture was stirred for 12 hours at 100° C.Then, the reaction mixture was cooled to room temperature, and treatedwith 20 mL of ethyl acetate. The organic layer was washed with water andsaturated saline solution, and dried over with anhydrous sodium sulfate.The solvent was removed under reduced pressure and the residue waspurified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 52 mg (52%) of the titlecompound.

Example 359N-{trans-4-[(Dimethylamino)methyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 92 mg (quantitative) was obtained in a manner similarto the Example 358 by use of 2M-dimethylamine/tetrahydrofuran solution,instead of morpholine.

Example 360N-{trans-4-[(4-Acetyl-1-piperazinyl)methyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 82 mg (87%) was obtained in a manner similar to theExample 358 by use of 1-acetylpiperazine, instead of morpholine.

Example 361N-{3-[(Dimethylamino)sulfonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazole-5-carboxamide

The title compound 133 mg (66%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example67 and the compound obtained in the Example 195, instead of benzylamineand the compound obtained in the Example 6, respectively.

Example 3623-Methyl-N-[3-(methylsulfonyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 74 mg (39%) was obtained in a manner similar to theExample 7 by use of 3-methylsulfonylaniline HCl salt and the compoundobtained in the Example 195, instead of benzylamine and the compoundobtained in the Example 6, respectively.

Example 363N-{3-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 135 mg (53%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example68 and the compound obtained in the Example 195, instead of benzylamineand the compound obtained in the Example 6, respectively.

Example 364N-[3-[(2-Hydroxyethyl)sulfonyl]phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 61 mg (60%) was obtained in a manner similar to theExample 266 by use of the compound obtained in the Example 363, insteadof the compound obtained in the Example 265.

Example 3651-cyclohexyl-N-[3-fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamidedimethanesulfonate

A mixture solution of 456.5 mg (1.00 mmol) of the compound obtained inthe Example 159 and 142.8 μL (2.20 mmol) of methanesulfonic acid in 4 mLof ethanol was condensed under reduced pressure. The residue was treatedwith 5 mL of ethanol and the residue was solved in the solution byheating and refluxing. Then, 2 mL of isopropyl ether was added and themixture was cooled gradually to room temperature. The resultingprecipitates were collected by filtration to give 383 mg (59%) of thetitle compound.

Example 3661-Cyclohexyl-N-[3-fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamidep-toluenesulfonate

To a solution of 228.3 mg (0.50 mmol) of the compound obtained in theExample 159 in 2 mL of ethanol was added 104.6 mg (0.55 mmol) ofp-toluenesulfonic acid monohydrate at 50° C., and the mixture wascondensed under reduced pressure. Then, 1.5 mL of isopropanol was addedto the residue and the residue was solved in the mixture by heating at70° C., and the mixture was cooled gradually to room temperature. Theresulting precipitates were collected by filtration to give 281 mg (89%)of the title compound.

Example 3671-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamidemethanesulfonate

To a solution of 438.6 mg (1.00 mmol) of the compound obtained in theExample 114 in 4 mL of ethanol was added 71.4 μL (1.10 mmol) ofmethanesulfonic acid, and further 0.8 mL of ethyl acetate was added tothe mixture. After refluxing the mixture, then, the mixture was cooledgradually to room temperature. The resulting precipitates were collectedby filtration to give 424 mg (79%) of the title compound.

Example 3681-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamidep-toluenesulfonate

To a suspension of 219.3 mg (0.50 mmol) of the compound obtained in theExample 114 in 3 mL of ethanol was added 104.6 mg (0.55 mmol) ofp-toluenesulfonic acid monohydrate, and the mixture was refluxed. Then,the separated precipitates were dissolved by adding 0.6 mL of water andthe mixture was cooled gradually to 0° C. The resulting precipitateswere collected by filtration to give 244 mg (80%) of the title compound.

Example 3693-Methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 120 mg (0.45 mmol) of the compound obtained in theExample 195 in 2 mL of 1,2-dichloroethane was added 66 μL (0.90 mmol) ofthionyl chloride and the mixture was refluxed for 2 hours. After coolingthe reaction mixture and the solvent removed under reduced pressure togive acid chloride intermediate compound.

314 μL (2.25 mmol) of triethylamine and 139 mg (0.54 mmol) of thecompound obtained in the Manufacturing Example 64 were added to thesolution of the acid chloride intermediate compound in 5 mL of anhydrousdichloromethane, and the mixture was stirred for 3 hours at roomtemperature. The reaction mixture was treated with saturated sodiumbicarbonate aqueous solution and extracted with dichloromethane. Theorganic layer was washed with water and saturated saline solution, then,dried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=20/1 to 10/1) to give172 mg (88%) of the title compound.

Example 3701-Cyclohexyl-N-[6-(4-hydroxy-1-piperidinyl)-3-pyridinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 216 mg (quantitative) was obtained in a mannersimilar to the Example 7 by use of the compound obtained in theManufacturing Example 74, instead of benzylamine.

Example 3711-Cyclohexyl-N-[2,3-difluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 177 mg (82%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example76, instead of benzylamine.

Example 3721-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl-3-methylphenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 189 mg (92%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example78, instead of benzylamine.

Example 373N-[3-Cyano-4-(4-hydroxy-1-piperidinyl)phenyl]-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 209 mg (99%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example80, instead of benzylamine.

Example 374 Methyl5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-2-(4-hydroxy-1-piperidinyl)benzoate

The title compound 224 mg (99%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example82, instead of benzylamine.

Example 3755-{[(1-Cyclohexoyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-(4-hydroxy-1-piperidinyl)benzoicacid

The title compound 167 mg (81%) was obtained in a manner similar to theExample 41 by use of the compound obtained in the Example 374, insteadof the compound obtained in the Example 40.

Example 376N-[6-(4-Hydroxy-1-piperidinyl)-3-pyridinyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 202 mg (quantitative) was obtained in a mannersimilar to the Example 369 by use of the compound obtained in theManufacturing Example 74, instead of the compound obtained in theManufacturing Example 64.

Example 377 3-Methyl-1-tetrahydro-2H-pyran-4-yl-N-(1-tetrahydro2H-pyran-4-yl-4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 187 mg (96%) was obtained in a manner similar to theExample 369 by use of the compound obtained in the Manufacturing Example84, instead of the compound obtained in the Manufacturing Example 64.

Example 3781-Cyclohexyl-N-{6-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyridinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 100 mg (0.26 mmol) of the compound obtained in theExample 103 in 5 mL of anhydrous dichloromethane were added 39.4 mg(0.39 mmol) of 4-hydroxypiperidine, 53 mg (0.39 mmol) of1-hydroxybenzotriazole, 74.8 mg (0.39 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl salt and 72.5 μL (0.52mmol) of triethylamine, and the mixture was stirred for 17 hours at roomtemperature. The reaction mixture was treated with saturated sodiumbicarbonate aqueous solution, and extracted with dichloromethane. Theorganic layer was washed with water and saturated saline solution, then,dried over with anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=10/1) to give 102 mg(84%) of the title compound.

Example 3791-Cyclohexyl-N-(6-{[(2-hydroxyethyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 76 mg (68%) was obtained in a manner similar to theExample 378 by use of 2-aminoethanol, instead of 4-hydroxypiperidine.

Example 380 1-Cyclohexyl-3-methylN-{6-[(4-methyl-1-piperazinyl)carbonyl]-3-pyridinyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 87 mg (72%) was obtained in a manner similar to theExample 378 by use of N-methylpiperazine, instead of4-hydroxypiperidine.

Example 3811-Cyclohexyl-N-[6-({[2-(dimethylamino)ethyl]amino}carbonyl-3-pyridinyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 71 mg (60%) was obtained in a manner similar to theExample 378 by use of N,N-dimethylethylenediamine, instead of4-hydroxypiperidine.

Example 3821-Cyclohexyl-N-(6-{[(trans-4-hydroxycyclohexyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 50 mg (39%) was obtained in a manner similar to theExample 378 by use of trans-4-aminocyclohexanol, instead of4-hydroxypiperidine.

Example 383 1-Cyclohexyl-3-methyl N-{6-[(4-methyl-1,4-diazepam-1-ylcarbonyl]-3-pyridinyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 105 mg (84%) was obtained in a manner similar to theExample 378 by use of N-methylhomopiperazine, instead of4-hydroxypiperidine.

Example 384 tert-Butyl4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}-1-piperidinecarboxylate

The title compound 1.86 g (92%) was obtained in a manner similar to theExample 369 by use of 4-amino-1-Boc-piperidine, instead of the compoundobtained in the Manufacturing Example 64.

Example 3853-Methyl-N-(4-piperidin)-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazole-5-carboxamide

A mixture solution of 1.81 g (4.03 mmol) of the compound obtained in theExample 384 in 10 mL of 4M-HCl/dioxane was stirred for 30 minutes atroom temperature and for 2 hours at 60° C. After cooling the reactionmixture, the solvent was removed under reduced pressure and the residuewas treated with saturated sodium bicarbonate aqueous solution, then,the mixture was extracted with chloroform. The organic layer was washedwith water and saturated saline solution and then, dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureto give 1.22 g (87%) of the title compound.

Example 386N-{1-[(Dimethylamino)carbonyl]-4-piperidinyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 132 mg (91%) was obtained in a manner similar to theExample 322 by use of the compound obtained in the Example 385, insteadof the compound obtained in the Example 321.

Example 387 tert-Butyl4-{4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}piperidin-1-yl}-1-piperidinecarboxylate

To a suspension of 220 mg (0.63 mmol) of the compound obtained in theExample 385 in 5 mL of 1,2-dichloroethane were added 15 μL of aceticacid and 151 mg (0.757 mmol) of 1-Boc-4-piperidone, and the mixture wasstirred for 30 minutes at room temperature. Then, 200 mg (0.95 mmol) ofsodium triacetoxyborohydride was added to the reaction mixture, and themixture was stirred for 6 hours at room temperature. The reactionmixture was treated with saturated sodium bicarbonate aqueous solutionand extracted with dichloromethane. The organic layer was washed withwater and saturated saline solution, then, dried over with anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1) to give 230 mg (69%) of the titlecompound.

Example 3883-Methyl-N-(piperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 165 mg (98%) was obtained in a mariner similar to theExample 385 by use of the compound obtained in the Example 387, insteadof the compound obtained in the Example 384.

Example 3893-Methyl-N-(1-acetylpiperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 51 mg (62%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example388, instead of the compound obtained in the Manufacturing Example 2.

Example 3903-Methyl-N-(1-methanesulfonylpiperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 68 mg (77%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example388 and methanesulfonyl chloride, instead of the compound obtained inthe Manufacturing Example 2 and acetyl chloride, respectively.

Example 391 tert-Butyl4-(trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate

The title compound 456 mg (46%) was obtained in a manner similar to theExample 369 by use of the compound obtained in the Manufacturing Example86, instead of the compound obtained in the Manufacturing Example 64.

Example 392 tert-Butyl4-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate

523 mg (52%) of the title compound was obtained as by-product in theExample 391.

Example 3933-Methyl-N-[trans-4-(1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamidedi-HCl salt

A mixture of 419 mg (0.817 mmol) of the compound obtained in the Example391 in 3 mL of 4M-HCl/dioxane and 1 mL of methanol was stirred for 5hours at room temperature. The solvent was removed under reducedpressure and the residue was treated with ethanol. The resultingprecipitates were collected by filtration to give 343 mg (83%) of thetitle compound.

Example 3943-Methyl-N-[cis-4-(1-piperazinyl)cyclohexyl]-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamidedi-HCl salt

The title compound 234 mg (51%) was obtained in a manner similar to theExample 393 by use of the compound obtained in the Example 392, insteadof the compound obtained in the Example 391.

Example 395N-[trans-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 100 mg (70%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example388 and acetic anhydride, instead of the compound obtained in theManufacturing Example 2 and acetyl chloride, respectively.

Example 3963-Methyl-N-{trans-4-[4-(methylsulfonyl)-1-piperazinyl]cyclohexyl}-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 109 mg (71%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example393 and methanesulfonyl chloride, instead of the compound obtained inthe Manufacturing Example 2 and acetyl chloride, respectively.

Example 397N-[cis-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-3-methyl-2-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 113 mg (66%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example394 and acetic anhydride, instead of the compound obtained in theManufacturing Example 2 and acetyl chloride, respectively.

Example 3983-Methyl-N-[1-(4-morpholinylcarbonyl)-4-piperidinyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 109 mg (69%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example385 and 4-morpholinyl chloride, instead of the compound obtained in theManufacturing Example 2 and acetyl chloride, respectively.

Example 3993-Methyl-N-{1-[(4-methyl-1-piperazinyl)carbonyl]-4-piperidinyl}-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 92 mg (56%) was obtained in a manner similar to theManufacturing Example 3 by use of the compound obtained in the Example385 and 4-methyl-1-piperazinecarbonyl chloride HCl salt, instead of thecompound obtained in the Manufacturing Example 2 and acetyl chloride,respectively.

Example 400N-(trans-4-Hydroxycyclohexyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 843 mg (52%) was obtained in a manner similar to theExample 396 by use of trans-4-aminocyclohexanol, instead of the compoundobtained in the Manufacturing Example 64.

Example 4013-Methyl-N-(4-oxocyclohexyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 828 mg (2.28 mmol) of the compound obtained in theExample 400 in 30 mL of dichloromethane were added 983 mg (4.56 mmol) ofpyridinium chlorochromate and 2 g of Molecular sieves 4A, and themixture was stirred for 4 hours at room temperature. The reactionmixture was filtrated by Celite®, and the filtrate was removed underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: dichloromethane/ethyl acetate) and furtherpurified by silica gel column chromatography (eluent: ethyl acetate) togive 668 mg (81%) of the title compound.

Example 402N-[trans-4-(cis-2,6-Dimethylmorpholinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.415 mmol) of the compound obtained in theExample 401 in 3 mL of 1,2-dichloroethane were added 103 μL (0.83 mmol)of cis-2,6-dimethylmorpholine and 15 μL of acetic acid, and the mixturewas stirred for 30 minutes at room temperature. Then, 132 mg (0.623mmol) of sodium triacetoxyborohydride was added to the reaction mixtureand the mixture was stirred for 4 hours at room temperature. Thereaction mixture was treated with saturated sodium bicarbonate aqueoussolution and extracted with dichloromethane. The organic layer waswashed with water and saturated saline solution, then, dried over withanhydrous sodium sulfate. The organic layer was removed under reducedpressure and the residue was purified by alkaline silica gel columnchromatography (eluent: ethyl acetate/hexane=1/1) to give 132 mg (69%)of the title compound.

Example 403N-[cis-4-(cis-2,6-Dimethylmorpholinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 46 mg (24%) was obtained in the Example 402 asby-product.

Example 4041-Cyclohexyl-N-[6-(hydroxymethyl)-3-pyridinyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 215 mg (58%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example87, instead of benzylamine.

Example 405 Methyl5-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}-2-pyridinecarboxylate

To a suspension of 700 mg (2.63 mmol) of the compound obtained in theExample 195 in 6 mL of 1,2-dichloroethane was added 384 μL (5.26 mmol)of thionyl chloride, and the mixture was refluxed for 2 hours. Afterreaction mixture was cooled, the solvent was removed under reducedpressure to give acid chloride intermediate compound.

Then, to a solution of the acid chloride intermediate compound obtainedabove in 8 mL of pyridine was added 400 mg (2.63 mmol) of methyl5-amino-2-pyridinecarboxylate, and the mixture was stirred for 2 hoursat room temperature. The reaction mixture was treated with saturatedsodium bicarbonate aqueous solution and extracted with dichloromethane.The organic layer was washed with water and saturated saline solution,then, dried over with anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the residue was purified by silica gel columnchromatography (eluent: ethyl acetate) to give 956 mg (91%) of the titlecompound.

Example 4065-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}-2-pyridinecarboxylicacid

To a solution of 923 mg (2.30 mmol) of the compound obtained in theExample 405 in 5 mL of methanol was added 5 mL of 1M-NaOH aqueoussolution, and the mixture was stirred for 1.5 hours at 60° C. Aftercooling the reaction mixture, the solvent was removed under reducedpressure and the residue was neutralized by adding 2.5 mL of 2M-HClaqueous solution. The resulting precipitates were collected to give 870mg (98%) of the title compound.

Example 407N-(6-{[(trans-4-Hydroxycyclohexyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 118 mg (94%) was obtained in a manner similar to theExample 378 by use of the compound obtained in the Example 406 andtrans-4-aminocyclohexanol, instead of the compound obtained in theExample 103 and 4-hydroxypiperidine, respectively.

Example 408N-[6-({[2-(Dimethylamino)ethyl]amino}carbonyl)-3-pyridinyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 108 mg (91%) was obtained in a manner similar to theExample 378 by use of the compound obtained in the Example 406 andN,N-dimethylethylenediamine, instead of the compound obtained in theExample 103 and 4-hydroxypiperidine, respectively.

Example 4093-Methyl-N-(6-{[(1-methyl-4-piperidinyl)amino]carbonyl}-3-pyridinyl)-1-tetrahydro-2H-pyran-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 35.6 mg (36%) was obtained in a manner similar to theExample 378 by use of the compound obtained in the Example 406 and4-amino-1-methylpiperidine, instead of the compound obtained in theExample 103 and 4-hydroxypiperidine, respectively.

Example 410N-(6-{[(1-Acetyl-4-piperidinyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 109 mg (82%) was obtained in a manner similar to theExample 378 by use of the compound obtained in the Example 406 and4-amino-1-acetylpiperidine, instead of the compound obtained in theExample 103 and 4-hydroxypiperidine, respectively.

Example 4111-cyclohexyl-3-methyl-N-[6-(4-morpholinylmethyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 120 mg (0.324 mmol) of the compound obtained in theExample 404 in 3 mL of ethyl acetate were added 90 μL (0.648 mmol) oftriethylamine and 38 μL (0.486 mmol) of methanesulfonyl chloride, andthe mixture was stirred for 30 minutes at room temperature. The reactionmixture was treated with ethyl acetate, and the organic layer was washedwith saturated sodium bicarbonate aqueous solution, water and saturatedsaline solution, respectively, then, dried over with anhydrous sodiumsulfate. Sodium sulfate was removed off by filtration, and the filtratewas treated with 1 mL of 4M-HCl/dioxane, and the solvent was removed togive(5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-yl)carbonyl]amino}-2-pyridinyl)methylmethanesulfonate HCl salt as the intermediate compound.

To a suspension of the intermediate compound obtained above in 3 mL ofacetonitrile were added 162 mg (1.17 mmol) of potassium carbonate, 28.8μL (0.33 mmol) of morpholine and 5.8 mg (0.035 mmol) of potassiumiodide, and then, the mixture was stirred for 2 hours at 70° C. and for15 hours at room temperature. Then, the reaction mixture was treatedwith water and extracted with ethyl acetate. The organic layer waswashed with water and saturated saline solution, and dried over withanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=10/1) to give 114 mg (80%) of thetitle compound.

Example 4121-Cyclohexyl-3-methyl-N-[6-(4-morpholinylmethyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamidemethanesulfonate

To a solution of 100 mg (0.227 mmol) of the compound obtained in theExample 411 in 2 mL of ethanol was added 14.8 μL of methanesulfonic acidand the solvent was removed. The residue was recrystallized fromisopropanol to give 77 mg (63%) of the title compound.

Example 4131-Cyclohexyl-N-{6-[(4-hydroxy-1-piperidinyl)methyl]-3-pyridinyl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 104 mg (71%) was obtained in a manner similar to theExample 411 by use of 4-hydroxypiperidine, instead of morpholine.

Example 414N-{6-[(4-Acetyl-1-piperazinyl)methyl]-3-pyridinyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 102 mg (66%) was obtained in a manner similar to theExample 411 by use of l-acetylpiperazine, instead of morpholine.

Example 4153-Methyl-N-[trans-4-(4-methyl-2-oxo-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 124 mg (72%) was obtained in a manner similar to theExample 369 by use of the compound obtained in the Manufacturing Example91, instead of the compound obtained in the Manufacturing Example 64.

Example 4161-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-2-oxo-1-piperazinyl)-cyclohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 130 mg (75%) was obtained in a manner similar to theExample 7 by use of the compound obtained in the Manufacturing Example91, instead of benzylamine.

Example 4173-Methyl-N-[trans-4-(3-oxo-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 115 mg (62%) was obtained in a manner similar to theExample 402 by use of 2-piperazine, instead ofcis-2,6-dimethylmorpholine.

Example 4183-Methyl-N-[cis-4-(3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 43 mg (23%) was obtained in the Example 471, asby-product.

Example 4193-Methyl-N-[trans-4-(4-methyl-3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a suspension of 150 mg (0.415 mmol) of the compound obtained in theExample 401 in 3 mL of 1,2-dichloroethane were added 125 mg (0.83 mmol)of 1-methyl-2-piperazinone HCl salt, 15 μL of acetic acid, and 82 mg(1.0 mmol) of sodium acetate, and the mixture was stirred for 30 minutesat room temperature. Then, 132 mg (0.623 mmol) of sodiumtriacetoxyborohydride was added to the reaction mixture, and the mixturewas stirred for 1 hour at room temperature. The react ion mixture wasdiluted by saturated sodium bicarbonate aqueous solution and extractedwith dichloromethane. The organic layer was washed with water andsaturated saline solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1) to give 131 mg (69%) of the titlecompound.

Example 4203-Methyl-N-[cis-4-(4-meth-3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 21 ng (11%) was obtained in the Example 419, asby-product.

Example 421 Ethyl1-(trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylate

The title compound 690 mg (37%) was obtained in a manner similar to theExample 369 by use of the compound obtained in the manufacturing Example93, instead of the compound obtained in the Manufacturing Example 64.

Example 422 Ethyl1-(cis-4-{([(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylate

The title compound 1.10 g (58%) was obtained in the Example 421, asby-product.

Example 423N-{trans-4-[4-(Hydroxymethyl)-1-piperidinyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-1-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 59 mg (54%) was obtained in a manner similar to theExample 206 by use of the compound obtained in the Example 421, insteadof the compound obtained in the Example 204.

Example 424N-{cis-4-[4-(Hydroxymethyl)-piperidinyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 61 mg (55%) was obtained in a manner similar to theExample 206 by use of the compound obtained in the Example 422, insteadof the compound obtained in the Example 204.

Example 425N-[trans-4-(4-Hydroxy-1-piperidinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 76 mg (42%) was obtained in a manner similar to theExample 402 by use of 4-hydroxypiperidine, instead ofcis-2,6-dimethylmorpholine.

Example 426N-(cis-4-{4-[(Dimethylamino)carbonyl]-1-piperidinyl}cyclohexyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

A mixture solution of 400 mg (0.795 mmol) of the compound obtained inthe Example 422 in 8 mL of 6M-HCl aqueous solution was refluxed for 2.5hours. After cooling the reaction mixture, the solvent was removed underreduced pressure to give1-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylicacid HCl salt as intermediate compound.

Then, to a suspension of the intermediate compound obtained above indichloromethane were added 0.60 mL (1.2 mmol) of2M-dimethylamine/tetrahydrofuran, 229 mg (1.19 mmol) of1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl salt, 0.746 μL (5.35mmol) of triethylamine and 182 mg (1.19 mmol) of 1-hydroxybenzotriazole,and the mixture was stirred for 95 hours at room temperature. Thesaturated sodium bicarbonate aqueous solution was added to the reactionmixture, and the mixture was extracted with dichloromethane. The organiclayer was washed water and saturated saline solution, then, dried overwith anhydrous sodium sulfate. The solvent was removed under reducedpressure and the residue was purified by alkaline silica gel columnchromatography (eluent: ethyl acetate) to give 196 mg (49%) of the titlecompound.

Example 4271-(trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylicacid HCl salt

A mixture solution of 400 mg (0.795 mmol) of the compound obtained inthe Example 421 in 6M-HCl aqueous solution was stirred for 2 hours at70° C. The solvent was removed to give 465 mg (quantitative) of thetitle compound.

Example 428N-(trans-4-{4-[(Dimethylamino)carbonyl]-1-piperidinyl}cyclohexyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 195 mg (78%) was obtained in a manner similar to theExample 378 by use of the compound obtained in the Example 427 and2M-dimethylamine/tetrahydrofuran, instead of the compound obtained inthe Example 103 and 4-hydroxypiperidine, respectively.

Example 429 N′-(Dihydro-2H-pyran-3(4H)-ylidene)benzohydrazide

To a solution of 3.48 g (34.1 mmol) of tetrahydro-2H-pyran-3-ol in 350mL of dichloromethane were added 11.1 g (51.2 mmol) of pyridiniumchlorochromate, 3.16 g (38.5 mmol) of sodium acetate, and 30 g ofmolecular sieve 4A, and the mixture was stirred for 4 hours at roomtemperature. Then, the reaction mixture was filtrated by Celite® and thefiltrate was condensed under reduced pressure. The residue was purifiedby silica gel column chromatography (eluent: hexane/ethyl acetate=2/1)to give dihydro-2H-pyran-3(4H)-one as intermediate compound.

A mixture solution of the intermediate compound obtained above and 4.6 g(34.1 mmol) of benzoylhydrazine in 20 mL of methanol was stirred for 4hours at 60° C. After cooling the reaction mixture, the solvent wasremoved and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=30/1) to give 1.75 g (24%) of thetitle compound.

Example 430 N′-Tetrahydro-2H-pyran-3-ylbenzohydrazide

To a solution of 1.64 g (7.51 mmol) of the compound obtained in theExample 429 in methanol was added 257 mg (6.76 mmol) of sodiumborohydride at 0° C., and the mixture was stirred for 3 hours at thesame temperature. The solvent was removed and the residue was treatedwith water and the mixture was extracted with dichloromethane. Theorganic layer was washed with water and saturated saline solution, then,dried over with anhydrous sodium sulfate. The solvent was removed andthe residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 1.46 g (88%) of the titlecompound.

Example 4315-Methyl-2-tetrahydro-2H-pyran-3-yl-2,4-dihydro-3H-pyrazol-3-one

To a solution of 1.44 g (6.53 mmol) of the compound obtained in theExample 430 in 10 mL of water was added 20 mL of conc. HCl, and themixture was stirred for 24 hours at 100° C. After cooling the reactionmixture, the insoluble substances were removed off by filtration, andthe filtrate was condensed to give 1-(tetrahydro-2H-pyran-3-yl)hydrazineHCl salt as intermediate compound.

A mixture of the intermediate compound obtained above and 705 μL (6.53mmol) of methyl acetoacetate was stirred for 2 hours at 110° C. Thereaction mixture was cooled and diluted with water and ethyl acetate,then, neutralized by 1M-NaOH aqueous solution. The solvent was removedand the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/1) to give 793 mg (67%) of thetitle compound.

Example 4325-Chloro-3-methyl-1-tetrahydro-2H-pyran-3-yl-1H-pyrazole-4-carboxaldehyde

The title compound 452 mg (47%) was obtained in a manner similar to theExample 193 by use of the compound obtained in the Example 431, insteadof the compound obtained in the Example 192.

Example 433 Ethyl3-methyl-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxylate

To a solution of 259 μL (2.36 mmol) of ethyl thioglycolate in 4 mL oftetrahydrofuran was added 94 mg (2.36 mmol) of sodium borohydride (60%oily) at 0° C., and the mixture was stirred for 30 minutes at roomtemperature. Then, the reaction mixture was cooled to 0° C. and 415 mg(1.81 mmol) of the compound obtained in the Example 432 in 4 mL oftetrahydrofuran was added gradually to this mixture, and the mixture wasstirred for 2 hours at room temperature. Then, the reaction mixture wascooled to 0° C. and 94 mg (2.36 mmol) of sodium borohydride (60% oily)was added to this mixture, and the mixture was stirred for 30 minutes atroom temperature. The reaction mixture was treated with ice water andextracted with ethyl acetate. The organic layer was washed with waterand saturated saline solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent: hexane/ethylacetate=3/1) to give 413 mg (78%) of the title compound.

Example 4343-Methyl-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxylicacid

The title compound 320 mg (89%) was obtained in a manner similar to theExample 6 by use of the compound obtained in the Example 433, instead ofthe compound obtained in the Example 5.

Example 4353-Methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 185 mg (95%) was obtained in a manner similar to theExample 369 by use of the compound obtained in the Example 434, insteadof the compound obtained in the Example 195.

Example 436N-[trans-4-(4-Ethyl-3-oxo-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 140 mg (71%) was obtained in a manner similar to theExample 419 by use of 1-ethyl-2-piperazinone HCl salt, instead of1-methyl-2-piperazinone HCl salt.

Example 437N-[cis-4-(4-Ethyl-3-oxo-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 41 mg (21%) was obtained in the Example 436, asby-product.

Example 438N-{trans-4-[(4-Ethyl-3-oxo-1-piperazinyl)methyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

To a solution of 150 mg (0.282 mmol) of the compound obtained in theExample 357 in 3 mL of N,N-dimethylformamide were added 93 mg (0.564mmol) of 1-ethyl-2-piperazinone HCl salt, and 236 μL (1.7 mmol) oftriethylamine, and the mixture was stirred for 5 hours at 100° C. Then,43 mg (0.282 mmol) of sodium iodide was added to the reaction mixtureand the mixture was stirred for 40 hours at 100° C. Further, 100 mg(0.61 mmol) of 1-ethyl-2-piperazinone HCl salt and 50 mg (0.33 mmol) ofsodium iodide were added to the reaction mixture, and the mixture wasstirred for 15 minutes at 120° C. using microwave. After the reaction,water was added to the reaction mixture and the mixture was extractedwith dichloromethane. The organic layer was washed with water andsaturated saline solution, then, dried over with anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1 to 15/1), and further alkaline silica gelcolumn chromatography (eluent: ethyl acetate) to give 63 mg (46%) of thetitle compound.

Example 4393-Methyl-N-{trans-4-[(4-methyl-3-oxo-1-piperazinyl)methyl]-cyclohexyl}-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The title compound 24 mg (18%) was obtained in a manner similar to theExample 438 by use of l-methyl-2-piperazinone HCl salt, instead of1-ethyl-2-piperazinone HCl salt.

Example 4403-Methyl-N-[4-(4-methyl-2-oxo-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide

The free base of the title compound was obtained in a manner similar tothe Example 7 by use of the compound obtained in the ManufacturingExample 72 and the compound obtained in the Example 195, instead ofbenzylamine and the compound obtained in the Example 6, respectively.Then, 30.7 μL (0.473 mmol) of methanesulfonic acid was added to asolution of the free base of the compound obtained above in 2.5 mL ofisopropanol, and the mixture was refluxed. The reaction mixture wascooled to room temperature and the resultant precipitates were collectedto give 206 mg (83%) of the title compound.

Chemical structure and physicochemical data of the compounds obtained bythe above-mentioned Manufacturing Examples and Examples are summarizedin the following Tables.

TABLE 5 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 1

pale yellow cryst. 98-100 COCl₃ 1.58 (9H, s), 3.17 (2H, t, J = 8.8 Hz),4.09 (2H, t, J = 8.8 Hz), 7.76-7.82 (1H, m), 8.00-8.02 (1H, m), 8.10(1H, m) 265 2

brown oil CDCl₃ 1.53 (9H, s), 3.00 (2H, t, J = 8.6 Hz), 3.45 (2H, brs),3.88-3.98 (2H, m), 6.45-6.56 (2H, m), 7.58-7.65 (1H, m) 234 3

colorless cryst. 134-138 CDCl₃ 1.57 (9H, s), 2.15 (3H, s), 3.06 (2H, t,J = 8.7 Hz), 3.91-4.05 (2H, m), 6.90-7.11 (2H, m), 7.50-7.71 (1H, m) 2774

pale pink cryst. 195-210 DMSO 2.06 (3H, s), 3.18 (2H, t, J = 7.8 Hz),3.70 (2H, t, J = 7.8 Hz), 7.35-7.38 (1H, m), 7.50-7.53 (1H, m),7.76-7.78 (1H, m), 10.24 (1H, brs), 11.18 (2H, brs) 177

TABLE 6 Properties m.p. (° C.) Manufacturing (recryst. MS(FAB) ExampleNo. Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 5

colorless cryst. 247-249 DMSO 1.13 (6H, d, J = 6.6 Hz), 3.99-4.09 (1H,m), 6.38-6.41 (3H, m), 7.79 (1H, dd, J = 2.3 and 8.6 Hz), 7.84 (1H, d, J= 7.6 Hz), 8.43 (1H, d, J = 2.3 Hz) 180 6

pale yellow 190-192 CDCl₃ 2.99 (3H, s), 3.26 (2H, t, J = 8.6 Hz), 4.13(2H, t, J = 8.6 Hz), 7.47 (1H, d, J = 8.9 Hz), 8.07-8.09 (1H, m),8.13-8.16 (1H, m) 243 7

yellow crys. 117-118 CDCl₃ 2.79 (3H, s), 3.05 (2H, t, J = 8.3 Hz), 3.57(2H, brs), 3.94 (2H, t, J = 8.3 Hz), 6.53 (1H, dd, J = 2.2 and 8.4 Hz),6.58-6.60 (1H, m), 7.21 (1H, d, J = 8.4 Hz) 212 8

pale yellow cryst. 146-148 CDCl₃ 2.22 (1H, t, J = 5.3 Hz), 2.56 (2H, t,J = 5.3 Hz), 2,59-2.63 (4H, m), 3.08-3.13 (4H, m), 2.56-2.61 (2H, m),7.94-7.97 (2H, m), 8.39-8.42 (2H, m) 316

TABLE 7 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 9

pale yellow cryst. 114-116 CDCl₃ 2.02 (3H, s), 2.55-2.69 (6H, m),3.04-3.15 (4H, m), 4.13 (2H, t, J = 5.7 Hz), 7.94 (2H, dd, J = 1.8 and7.0 Hz), 8.39 (2H, dd, J = 1.8 and 7.0 Hz) 358 10

colorless cryst. 109-112 CDCl₃ 2.03 (3H, s), 2.53-2.68 (6H, m),2.94-3.07 (4H, m), 4.07-4.19 (4H, m), 6.67-6.70 (2H, m), 7.51-7.54 (2H,m) 328 11

colorless cryst. 210 (dec.) CDCl₃ 1.12-1.28 (4H, m), 1.44 (9H, s),1.92-2.05 (4H, m), 1.95 (3H, s), 3.33-3.45 (1H, m), 3.68- 3.78 (1H, m),4.32-4.42 (1H, m), 5.21-5.29 (1H, m) 257 12

colorless cryst. 230 (dec.) MeOH 1.26-1.55 (4H, m), 1.91 (3H, s),1.94-2.11 (4H, m), 3.01-3.12 (1H, m), 3.55-3.67 (1H, m), 7.99 (1H, d, J= 6.8 Hz) 157

TABLE 8 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 13

yellow solid 107-110 CDCl₃ 3.53 (3H, s), 4.06 (2H, m), 7.77 (2H, d, J =9.1 Hz), 8.22 (2H, d, J = 9.1 Hz), 8.56 (1H, brs) 211 14

brown solid 82-83 CDCl₃ 3.49 (3H, s), 3.61 (2H, brs), 3.99 (2H, s), 6.66(2H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 8.06 (1H, brs) 181 15

brown solid 73-78 CDCl₃ 2.34 (3H, s), 2.51-2.56 (4H, m), 3.29 (2H, brs),3.38-3.43 (4H, m), 6.57 (1H, d, J = 8.8 Hz), 6.98 (1H, dd, J = 3.0 and8.8 Hz), 7.79 (1H, d, J = 3.0 Hz) 193 16

pale yellow solid 104-105 CDCl₃ 2.28 (3H, s), 2.48-2.53 (4H, m),3.08-3.13 (4H, m), 7.73-7.80 (1H, m), 8.07-8.12 (1H, m), 8 44-8.49 (1H,m), 8.60-6.62 (1H, m) 286

TABLE 9 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 17

colorless solid 141-142 CDCl₃ 2.27 (3H, s), 2.45-2.50 (4H, m), 3.01-3.06(4H, m), 3.89 (2H, brs), 6.82-6.87 (1H, m), 7.00-7.03 (1H, m), 7.08-7.12(1H, m), 7.24-7.27 (1H, m) 256 18

yellow solid 49-50 CDCl₃ 3.13 (3H, s), 3.58-3.64 (2H, m), 3.87-3.93 (2H,m), 6.80-6.86 (1H, m), 7.89 (1H, dd, J = 1.5 and 14.3 Hz), 7.95- 8.00(1H, m) 215 19

brown oil CDCl₃ 2.73 (3H, s), 3.06-3.11 (2H, m), 3.59 (2H, brs),3.88-3.93 (2H, m), 6.37-6.454 (2H, m), 6.88-6.95 (1H, m) 185 20

yewllow oil CDCl₃ 1.47 (9H, s), 1.57-1.70 (2H, m), 1.78-1.90 (2H, m),2.70-2.86 (3H, m), 4.20-4.32 (2H, m), 7.34 (2H, d, J = 8.7 Hz), 8.15(2H, d, J = 8.7 Hz) 307

TABLE 10 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 21

pale yellow solid 109-112 CDCl₃ 1.46 (9H, s), 1.51-1.61 (2H, m),1.72-1.79 (2H, m), 2.47-2.57 (1H, m), 2.70-2.81 (2H, m), 3.56 (2H, brs),4.14-4.26 (1H, m), 6.63 (2H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.3 Hz)277 22

Yellow solid 64-65 CDCl₃ 1.12 (3H, t, J = 7.2 Hz), 2.47 (2H, q, J = 7.2Hz), 2.58-2.63 (4H, m), 3.29-3.34 (4H, m), 6.89 (1H, dd, J = 8.8 and 8.8Hz), 7.88 (1H, dd, J = 2.6 and 13.2 Hz), 7.95- 8.00 (1H, m) 254 23

yellow solid 49-50 CDCl₃ 2.00-2.07 (2H, m), 2.39 (3H, s), 2.58-2.63 (2H,m), 2.73-2.79 (2H, m), 3.54-3.60 (2H, m), 3.61-3.66 (2H, m), 6.68-8.74(1H, m), 7.83-7.94 (2H, m) 254 24

pale yellow solid 58-60 CDCl₃ 1.11 (3H, t, J = 7.2 Hz), 2.46 (2H, q, J =7.2 Hz), 2.57-2.64 (4H, m), 2.97-3.03 (4H, m), 3.51 (2H, brs), 6.35-6.45(2H, m), 7.77-7.84 (1H, m) 224

TABLE 11 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 25

pale yellow solid 71-71.5 CDCl₃ 2.36 (3H, s), 2.57-2.64 (4H, m),3.30-3.38 (4H, m), 6.88-6.94 (1H, m), 7.90 (1H, dd, J = 2.5 and 13.2Hz), 7.98 (1H, dd, J = 2.5 and 9.0 Hz) 240 26

pale reddish brown solid 93-94.5 CDCl₃ 2.34 (3H, s), 2.51-2.69 (4H, m),2.96-3.09 (4H, m), 3.53 (2H, brs), 6.37-6.48 (2H, m), 6.78-6.87 (1H, m)210 27

pale yellow solid 129-131 (AcOEt/hexane) CDCl₃ 1.84-1.92 (4H, m), 3.38-3.47 (4H, m), 4.01 (4H, s), 6.89-6.97 (1H, m), 7.90 (1H, dd, J = 2.6 and13.1 Hz), 7.97 (1H, dd, J = 2.6 and 8.8 Hz) 284 28

colorless solid 100.5-101.5 (EtOH) CDCl₃ 1.83-1.92 (4H, m), 3.01-3.09(4H, m), 3.53 (2H, brs), 3.99 (4H, s), 6.37-6.47 (2H, m), 6.79-6.88 (1H,m) 253

TABLE 12 Properties Manufacturing m.p.(° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 29

yellow solid 121-122 AcOEt/hexane) CDCl₃ 1.89-1.98 (4H, m), 3.27-3.34(4H, m), 4.02 (4H, s), 7.05 (1H, d, J = 8.9 Hz), 8.08 (1H, dd, J = 2.7and 8.9 Hz), 8.25 (1H, d, J = 2.7 Hz) 299 30

pale yellow solid 139.5-140.5 (EtOH) CDCl₃ 1.83-1.92 (4H, m), 2.97-3.04(4H, m), 3.52 (2H, brs), 4.00 (4H, s), 6.54 (1H, dd, J = 2.6 and 8.5Hz), 6.74 (1H, d, J = 2.6 Hz), 6.91 (1H, d, J = 8.5 Hz) 269 31

reddish brown solid 40-42 CDCl₃ 1.90-1.97 (2H, m), 2.33 (3H, s),2.65-2.75 (4H, m), 3.23-3.30 (4H, m), 3.43 (2H, brs), 6.32-6.42 (2H, m),6.72-6.78 (1H, m) 224 32

pale brown solid CDCl₃ 2.46-2.56 (6H, m), 2.66-2.73 (2H, m), 3.58 (2H,brs), 3.70-3.76 (4H, m), 6.59-6.65 (2H, m), 6.96- 7.02 (2H, m) 207

TABLE 13 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure recryst. solvent) ¹H-NMR (M + 1)⁺ 33

pale yellow viscous solid CDCl₃ 3.02 (3H, s), 3.92 (2H, s), 4.74 (2H,s), 7.54-7.59 (2H, m), 8.15-8.20 (2H, m) 250 34

pale yellow viscous solid CDCl₃ 2.96 (3H, s), 3.65 (2H, brs), 3.82 (2H,s), 4.53 (2H, s), 6.57-6.62 (2H, m), 7.22-7.27 (2H, m) 220 35

pale yellow solid CDCl₃ 1.10-1.22 (2H, m), 1.44 (9H, s), 1.61-1.73 (2H,m), 2.04-2.15 (4H, m), 2.36-2.45 (1H, m), 3.46 (1H, br), 4.38 (1H, br)225 36

colorless solid DMSO-d₆ 1.27-1.40 (2H, m), 1.51-1.65 (2H, m), 1.90-1.98(2H, m), 2.03-2.11 (2H, m), 2.67 (1H, tt, J = 3.7 and 11.7 Hz),2.94-3.07 (1H, m), 8.06 (3H, br) 125

TABLE 14 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 37

colorless solid D₂O 3.06 (3H, brs), 3.25-3.32 (2H, m), 3.67-3.99 (6H, m)172 38

colorless solid CDCl₃ 1.29-1.40 (2H, m), 1.45 (9H, s), 1.89-1.96 (2H,m), 2.88 (6H, s), 2.82-2.88 (2H, m), 3.57- 3.65 (3H, m), 4.43 (1H, br)272 39

colorless foamy solid DMSO-d₆ 1.39-1.51 (2H, m), 1.83-1.92 (2H, m), 2.50(3H, s), 2.68-2.78 (2H, m), 2.72 (3H, s), 3.08-3.21 (1H, m), 3.51-3.59(2H, m) 172 40

colorless solid CDCl₃ 1.39-1.49 (2H, m), 1.44 (9H, s), 1.93-2.02 (2H,m), 2.81 (6H, s), 2.88-2.89 (2H, m), 3.50- 3.68 (3H, m), 4.46 (1H, br)308

TABLE 15 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 41

colorless solid DMSO-d₆ 1.45-1.56 (2H, m), 1.88-1.96 (2H, m), 2.74 (6H,s), 2.86-2.96 (2H, m), 3.11-3.21 (1H, m), 3.56-3.62 (2H, m), 8.02 (3H,br) 208 42

colorless solid CDCl₃ 1.43 (9H, s), 1.80-1.87 (1H, m), 2.41 (1H, ddd, J= 7.2, 9.4 and 14.7 Hz), 2.92-2.99 (1H, m), 3.12 (1H, dd, J = 5.7 and11.0 Hz), 3.76 (3H, s), 3.82 (1H, dd, J = 4.8 and 9.4 Hz), 4.12 (1H,br), 4.92 (1H, br) 245 43

colorless solid CDCl₃ 1.44 (9H, s), 1.97-2.06 (1H, m), 2.47 (1H, ddd, J= 6.5, 9.5 and 13.9 Hz), 3.33-3.39 (1H, m), 3 70 (1H, dd, J = 6.0 and9.9 Hz), 3.79 (3H, s), 4.36-4.46 (1H, m), 4.43 (1H, dd, J = 2.7 and 9.5Hz), 4.60 (2H, brs), 5.52-5.58 (1H, m) 288 44

colorless solid CDCl₃ 1.45 (9H, s), 1.80-2.65 (2H, br), 3.25-4.80 (5H,br) 256

TABLE 16 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 45

colorless sold D₂O 1.94-2.04 (1H, m), 2.70-2.78 (1H, m), 3.64-3.75 (2H,m), 3.76 (1H, s), 4.25-4.34 (1H, m), 4.51 (1H, dd, J = 7.3 and 10.5 Hz)156 46

pale reddish brown solid CDCl₃ 3.42-3.58 (4H, m), 4.07-4.14 (2H, m),4.58 (1H, br), 7.06 (1H, dd, J = 2.9 and 8.9 Hz), 7.79 (1H, dd, J = 0.7and 2.9 Hz), 8.04 (1H, dd, J = 0.7 and 8.9 Hz) 179 47

pale brown solid DMSO-d₆ 3.99 (2H, s), 5.24 (2H, brs), 6.57 (2H, dd, J =2.0 and 6.6 Hz), 6.89 (1H, dd, J = 2.0 and 6.6 Hz), 8.10 (1H, brs) 19248

pale brown solid DMSO-d₆ 2.89 (3H, s), 4.04 (2H, s), 5.27 (2H, brs),6.55-6.60 (2H, m), 6.86-6.91 (2H, m) 206

TABLE 17 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 49

reddish brown solid CDCl₃ 1.98-2.06 (1H, m), 2.13-2.24 (1H, m),3.18-3.50 (6H, m), 4.52-4.58 (1H, m), 6.45-6.51 (1H, m), 6.64-6.70 (1H,m) 179 50

brown solid (EtOH) DMSO-d₆ 1.86-2.05 (2H, m), 3.38-3.45 (1H, m),3.55-3.74 (3H, m), 4.36-4.42 (1H, m), 5.05 (1H, d, J = 3.5 Hz) 6.74-6.80 (1H, m), 7.89-7.97 (2H, m) 227 51

purple oil CDCl₃ 1.90-1.99 (1H, m), 2.14-2.25 (1H, m), 3.06-3.27 (2H,m), 3.35-3.56 (2H, m), 4.47-4.52 (1H, m), 6.36-6.48 (2H, m), 6.57-6.64(1H, m) 197 52

pale brown solid DMSO-d₆ 1.38-1.48 (2H, m), 1.70-1.78 (2H, m), 2.78-2.85(2H, m), 3.19-3.26 (2H, m), 3.50-3.58 (1H, m), 4.69 (1H, d, J = 4.0 Hz),7.93-7.99 (1H, m), 8.17- 8.21 (1H, m), 8.36-8.38 (1H, m), 8.54- 8.58(1H, m) 287

TABLE 18 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 53

colorless solid DMSO-d₆ 1.39-1.48 (2H, m), 1.69-1.77 (2H, m), 2.65-2.73(2H, m), 3.06-3.15 (2H, m), 3.50-3.58 (1H, m), 4.65 (1H, d, J = 3.8 Hz),5.61 (2H, brs), 6.76-6.84 (2H, m), 6.89-6.92 (1H, m), 7.20-7.26 (1H, m)257 54

colorless solid DMSO-d₆ 1.38-1.48 (2H, m), 1.71-1.79 (2H, m), 2.81-2.88(2H, m), 3.18-3.26 (2H, m), 3.52-3.59 (1H, m), 4.68 (1H, d, J = 4.0 Hz),8.00-8.05 (2H, m), 8.42-8.47 (2H, m) 287 55

colorless solid CDCl₃ −0.01 (6H, s), 0.77 (9H, s), 1.59-1.68 (2H, m),1.77-1.87 (2H, m), 3.07-3.15 (2H, m), 3.17-3.24 (2H, m), 3.82-3.89 (1H,m), 7.93-7.98 (2H, m), 8.37-8.42 (2H, m) 401 56

colorless solid CDCl₃ −0.01 (6H, s), 0.80 (9H, s), 1.56-1.65 (2H, m),1.75-1.84 (2H, m), 2.89-2.96 (2H, m), 3.12-3.19 (2H, m), 3.72-3.78 (1H,m), 4.10 (2H, br), 6.68-6.73 (2H, m), 7.52-7.57 (2H, m) 371

TABLE 19 Properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 57

yellowish solid 56.5-57.5 CDCl₃ 2.36(3H, s), 2.52-2.64(4H, m),3.11-3.22(4H, m), 7.27(1H, d, J = 9.1 Hz), 8.31(1H, dd, J = 2.6 and 9.1Hz), 8.50(1H, d, J = 2.6 Hz) 290 58

reddish brown solid 123- 125 CDCl₃ 2.32(3H, s), 2.40-2.60(4H, m),2.80-2.89(4H, m), 3.69(2H, brs), 6.78(1H, dd, J = 2.7 and 8.5 Hz),6.89(1H, d, J = 2.7 Hz), 7.19(1H, d, J = 8.5 Hz) 260 59

colorless solid   154-156.5 CDCl₃ 2.66(3H, s), 3.28(2H, t, J = 6.5 Hz),3.35- 3.42(2H, m), 3.51(2H, t, J = 6.5 Hz), 3.88-3.95(2H, m),7.69-7.76(2H, m), 7.82-7.89(2H, m) 310 60

  HCl colorless solid 142-145 (EtOH) DMSO-d₆ 2.63(3H, s), 2.98-3.03(2H,m), 3.17- 3.43(6H, m), 8.02(3H, brs) 180(free)

TABLE 20 properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 61

yellowish solid 53-57 CDCl₃ 1.69-1.79(2H, m), 2.01-2.09(2H, m), 3.05-3.15(2H, m), 3.55-3.64(2H, m), 3.91-4.00(1H, m), 6.89- 6.96(1H, m),7.87-8.04(2H, m) 241 62

pale reddish brown solid 112-116 CDCl₃ 1.58(1H, br), 1.71-1.81(2H, m),1.98-2.06(2H, m), 2.71-2.81(2H, m), 3.17-3.25(2H, m), 3.53(2H, br),3.77-3.86(1H, m), 6.37-6.47(2H, m), 6.79-6.86(1H, m), 211 63

pale yellow solid 147-149 CDCl₃ 1.05-1.16(2H, m), 1.24-1.40(2H, m),1.43(9H, s), 1.86-1.97(2H, m), 2.02-2.10(2H, m), 2.16(1H, tt, J = 3.5and 11.4 Hz), 2.50-2.56(4H, m), 3.37(1H, br), 3.67-3.72(4H, m), 4.36(1H,br) 285 64

  2HCl colorless solid >250 DMSO-d₆ 1.32-1.48(2H, m), 1.51-1.66(2H, m),2.03- 2.12(2H, m), 2.17-2.26(2H, m), 2.90-3.20(4H, m), 3.33- 3.41(2H,m), 3.82-3.99(4H, m), 8.10-8.28(3H, m), 11.17-11.46(1H, m) 185

TABLE 21 properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 65

pale brown solid 195-199 DMSO-d₆ 3.32-3.37(2H, m), 3.62-3.67(2H, m),3.98(2H, s), 6.96-7.02(2H, m), 8.06-8.12(2H, m), 8.26(1H, brs) 222 66

pale brown solid CDCl₃ 3.28-3.33(2H, m), 3.45-3.51(2H, m), 3.74(2H, s),6.00(1H, brs), 6.65-6.71(2H, m), 6.77-6.83(2H, m). 192 67

pale purple solid 151-154 CDCl₃ 2.71(6H, s), 3.91(2H, br), 6.84-6.88(1H,m), 7.05-7.07(1H, m), 7.11-7.16(1H, m), 7.28-7.33(1H, m) 201 68

colorless solid 87-88 CDCl₃ −0.08(6H, s), 0.72(9H, s), 3.43(2H, t, J =5.6 Hz), 4.07(2H, t, J = 5.6 Hz), 7.74-7.80(1H, m), 8.24- 8.28(1H, m),8.47-8.52(1H, m), 8.77-8.79(1H, m) 346

TABLE 22 Manu- properties facturing m.p. (° C.) Exam- (recryst. MS(FAB)ple No. Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 69

colorless viscous solid CDCl₃ −0.01(6H, s), 0.81(9H, s), 3.33(2H, t, J =6.6 Hz), 3.94(2H, br), 3.98(2H, t, J = 6.6 Hz), 6.85-6.91 (1H, m),7.15-7.17(1H, m), 7.22-7.32(2H, m) 316 70

pale yellow solid CDCl₃ 1.77(1H, brs), 2.48(3H, s), 2.70(2H, t, J = 5.0Hz), 3.27(2H, s), 3.80(2H, brs), 7.78- 7.84(2H, m), 8.28-8.34(2H, m),9.97(1H, brs) 254 71

pale yellow solid 100-101 CDCl₃ 2.42(3H, s), 2.83(2H, t, J = 5.3 Hz),3.32(2H, s), 3.79(2H, t, J = 5.3 Hz), 7.53-7.59(2H, m), 8.24-8.30(2H, m)236 72

colorless solid 158-160 CDCl₃ 2.39(3H, s), 2.74-2.79(2H, m), 3.25(2H,s), 3.61-3.74(4H, m), 6.66-6.73(2H, m), 7.00-7.07(2H, m) 206

TABLE 23 properties Manufacturing m.p. (° C.) MS(FAB) Example No.Chemical Structure (recryst. solvent) ¹H-NMR (M + 1)⁺ 73

yellow solid 149-151 CDCl₃ 1.56-1.70(2H, m), 1.93-2.06(2H, m), 3.44-3.58(2H, m), 4.00-4.09(1H, m), 4.11-4.22(2H, m), 6.60(1H, d, J = 9.6Hz), 8.19(1H, dd, J = 2.8 and 9.6 Hz), 9.03(1H, d, J = 2.8 Hz) 224 74

reddish brown solid 140-140 CD₃OD 1.50-1.61(2H, m), 1.88-1.96(2H, m),2.88- 2.97(2H, m), 3.70-3.81(3H, m), 6.73(1H, d, J = 8.8 Hz), 7.10(1H,dd, J = 2.7 and 8.8 Hz), 7.70(1H, d, J = 2.7 Hz) 194 75

yellow solid 90.5-91.5 CDCl₃ 1.66-1.80(2H, m), 1.97-2.11(2H, m), 3.09-3.23(2H, m), 3.53-3.71(2H, m), 3.91-4.06(1H, m), 6.61- 6.72(1H, m),7.79-7.90(1H, m) 259 76

pale yellow solid 148-150 CD₃OD 1.62-1.73(2H, m), 1.90-2.00(2H, m),2.69- 2.79(2H, m), 3.12-3.21(2H, m), 3.65-3.74(1H, m), 6.52(1H, dt, J =2.2 and 8.9 Hz), 6.65(1H, dt, J = 2.2 and 8.8 Hz) 229

TABLE 24 Manu- properties facturing m.p. (° C.) Exam- (recryst. MS(FAB)ple No. Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 81

pale yellow oil CDCl₃ 1.69-1.80(2H, m), 1.99-2.10(2H, m), 3.08- 3.19(2H,m), 3.45-3.56(2H, m), 3.93(3H, s), 3.94- 4.004(1H, m), 6.98(1H, d, J =9.3 Hz), 8.19(1H, dd, J = 2.8 and 9.3 Hz), 8.60(1H, d, J = 2.8 Hz) 28182

pale yellow solid   123-124.5 CDCl₃ 1.47-1.53(1H, m), 1.67-1.78(2H, m),1.95- 2.02(2H, m), 2.70-2.79(2H, m), 3.10-3.19(2H, m), 3.50- 3.63(2H,m), 3.74-3.83(1H, m), 3.88(3H, s), 6.75(1H, dd, J = 2.9 and 8.6 Hz),6.91-6.98(1H, m), 7.03(1H, d, J = 2.9 Hz) 251 83

colorress solid 142-145 (EtOH) CDCl₃ 1.33-1.49(2H, m), 1.44(9H, s),1.52-1.63(2H, m), 1.70-1.79(2H, m), 1.90-1.99(2H, m), 2.19-2.28(2H, m),2.44(1H, tt, J = 3.8 and 11.4 Hz), 2.83-2.92(2H, m), 3.36(2H, dt, J =1.9 and 11.9 Hz), 3.41-3.50(1H, m), 3.99-4.05(2H, m), 4.39-4.48(1H, m)285 84

  2HCl colorless solid DMSO-d₆ 1.67-1.80(2H, m), 1.95-2.20(6H, m), 2.93-3.09(2H, m), 3.23-3.39(4H, m), 3.45-3.57(2H, m), 3.90- 4.02(2H, m),8.40-8.68(3H, m), 10.95-11.22(1H, m) 185(free)

TABLE 25 Manu- properties facturing m.p. (° C.) Exam- (recryst. MS(FAB)ple No. Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 81

pale yellow oil CDCl₃ 1.69-1.80(2H, m), 1.99-2.10(2H, m), 3.08- 3.19(2H,m), 3.45-3.56(2H, m), 3.93(3H, s), 3.94- 4.004(1H, m), 6.98(1H, d, J =9.3 Hz), 8.19(1H, dd, J = 2.8 and 9.3 Hz), 8.60(1H, d, J = 2.8 Hz) 28182

pale yellow solid   123-124.5 CDCl₃ 1.47-1.53(1H, m), 1.67-1.78(2H, m),1.95- 2.02(2H, m), 2.70-2.79(2H, m), 3.10-3.19(2H, m), 3.50- 3.63(2H,m), 3.74-3.83(1H, m), 3.88(3H, s), 6.75(1H, dd, J = 2.9 and 8.6 Hz),6.91-6.98(1H, m), 7.03(1H, d, J = 2.9 Hz) 251 83

colorress solid 142-145 (EtOH) CDCl₃ 1.33-1.49(2H, m), 1.44(9H, s),1.52-1.63(2H, m), 1.70-1.79(2H, m), 1.90-1.99(2H, m), 2.19-2.28(2H, m),2.44(1H, tt, J = 3.8 and 11.4 Hz), 2.83-2.92(2H, m), 3.36(2H, dt, J =1.9 and 11.9 Hz), 3.41-3.50(1H, m), 3.99-4.05(2H, m), 4.39-4.48(1H, m),285 84

  2HCl colorless solid DMSO-d₆ 1.67-1.80(2H, m), 1.95-2.20(6H, m), 2.93-3.09(2H, m), 3.23-3.39(4H, m), 3.45-3.57(2H, m), 3.90- 4.02(2H, m),8.40-8.68(3H, m), 10.95-11.22(1H, m) 185(free)

TABLE 26 Manu- properties facturing m.p. (° C.) Exam- (recryst. MS(FAB)ple No. Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 85

  cis, trans mixture pale yellow oil CDCl₃ 1.08-1.92(7H, m), 1.45(9H,s), 2.03-2.12(1H, m), 2.19-2.31(1H, m), 2.42-2.53(4H, m),3.37-3.50(4.5H, m), 3.74-3.83(0.5H, m), 4.57-4.64 (0.5H, m),4.83-4.91(0.5H, m), 5.05- 5.14(2H, m), 7.29-7.41(5H, m) 418 86

  cis, trans mixture colorless oil CDCl₃ 1.05-1.78(6H, m), 1.45 and1.46(9H, each s), 1.82-1.98(2H, m), 2.17-2.31(1H, m), 2.43-2.68(4.5H,m), 2.98-3.04(0.5H, m), 3.37-3.47 (4H, m) 284 87

  2HCl brown solid 145-148 DMSO-d₆ 4.66(2H, s), 7.60-7.70 (2H, m),7.94(1H, d, 2.4 Hz) 125(free) 88

colorless solid 215-217 (EtOH) CDCl₃ 1.18-1.38(4H, m), 1.44(9H, s),1.99-2.10(4H, m), 3.39-3.51(1H, m), 3.69-3.80(1H, m), 4.03(2H, s),4.37-4.46(1H, m), 6.35-6.42(1H, m) 291

TABLE 27 Manu- properties facturing m.p. (° C.) Exam- (recryst. MS(FAB)ple No. Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 89

colorless solid 161-163 (iso-PrOH) CDCl₃ 1.17-1.37(4H, m), 1.44(9H, s),1.92-2.13(5H, m), 2.33(3H, s), 2.58(2H, t, J = 5.2 Hz), 3.06(2H, s),3.35-3.48(1H, m), 3.69(2H, t, J = 5.2 Hz), 3.71-3.80(1H, m), 4.38-4.48(1H, m), 7.09-7.16(1H, m) 330 90

pale brown solid 162.5-165   CDCl₃ 1.21-1.37(2H, m), 1.44(9H, s),1.48-1.60(2H, m), 1.63-1.74(2H, m), 2.01-2.10(2H, m), 2.32(3H, s),2.59-2.65(2H, m), 3.11(2H, s), 3.20-3.27(2H, m), 3.30-3.44(1H, m),4.38-4.50(2H, m) 312 91

  2HCl colorless solid DMSO-d₆ 1.38-1.71(6H, m), 1.98- 2.09(2H, m),3.17(3H, s), 2.90-3.01 (1H, m), 3.20-3.90(6H, m), 4.11- 4.22(1H, m),8.09-8.28(3H, m), 11.92(1H, brs) 212(free) 92

  cis, trans mixture colorless gum CDCl₃ 1.06-1.97(14H, m), 2.02-2.31(5H, m), 2.81-2.98(2H, m), 3.37-3.49(0.4H, m), 3.74-3.87 (0.6H, m),4.08-4.18(2H, m), 4.53-4.62(0.4H, m), 4.83-4.93 (0.6H, m), 5.04-5.19(2H,m), 7.28-7.43(5H, m) 389

TABLE 28 Manu- properties facturing m.p. (° C.) Exam- (recryst. MS(FAB)ple No. Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 93

  cis, trans mixture colorless oil CDCl₃ 1.05-1.19(1H, m), 1.20-1.39(4H,m), 1.50- 1.97(12H, m), 2.12-2.32(4H, m), 2.62(0.4H, tt, J = 3.9 and11.1 Hz), 2.74-3.00(2H, m), 3.01-3.09(0.6H, m), 4.08-4.19(2H, m) 255 94

yello solid 106-107 (EtOH) CDCl₃ 1.53-1.56(1H, m), 1.62-1.72(2H, m),1.98- 2.06(2H, m), 3.21-3.29(2H, m), 3.76-3.84(2H, m), 3.97- 4.06(1H,m), 6.81-6.87(2H, m), 8.10-8.16(2H, m) 223 95

pale purple solid 171-173 CDCl₃ 1.45(1H, br), 1.68-1.77(2H, m),1.98-2.06(2H, m), 2.74-2.83(2H, m), 3.32-3.40(2H, m), 3.42(2H, br),3.76-3.85(1H, m), 6.63-6.68(2H, m), 6.81-6.86(2H, m) 193

TABLE 29 Properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 1

colorless cryst. 147.6-150.4 CDCl₃ 1.21-1.36(1H, m), 1.39-1.52(2H, m),1.71- 1.98(7H, m), 2.09(3H, s), 3.20(2H, s), 3.95-4.02(1H, m) 181 2

pale brown oil CDCl₃ 1.21-1.47(3H, m), 1.65-1.75(1H, m), 1.83- 1.95(6H,m), 2.23(3H, s), 4.10-4.20(1H, m), 5.95(1H, s) 3

colorless cryst. 86.0-87.6 CDCl₃ 1.21-1.50(3H, m), 1.71-1.79(1H, m),1.90- 1.98(6H, m), 2.46(3H, s), 4.18-4.28(1H, m), 9.88(1H, s) 227 4

colorless oil CDCl₃ 1.21(3H, t, J = 7.1 Hz), 1.22-1.50(3H, m), 1.71-2.01(7H, m), 2.48(3H, s), 3.59(2H, s), 4.12(2H, q, J = 7.1 Hz),4.58-4.60(1H, m), 10.02(1H, s) 311

TABLE 30 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 5

colorless oil CDCl₃ 1.22-1.34(1H, m), 1.38(3H, t, J = 7.1 Hz), 1.38-1.52(2H, m), 1.70-1.88(3H, m), 1.89-1.98(2H, m), 2.15- 2.22(2H, m),2.45(3H, s), 4.12-4.21(1H, m), 4.35(2H, q, J = 7.1 Hz), 7.70(1H, s) 2936

colorless cryst. 231.5-235.0 CDCl₃ 1.22-1.37(1H, m), 1.39-1.51(2H, m),1.72- 1.89(3H, m), 1.91-1.98(2H, m), 2.16-2.24(2H, m), 2.47(3H, s),4.16-4.25(1H, m), 7.79(1H, s) 265 7

colorless cryst. 128.4-130.1 CDCl₃ 1.21-1.33(1H, m), 1.38-1.51(2H, m),1.70- 1.87(3H, m), 1.89-1.95(2H, m), 2.14-2.21(2H, m), 2.42(3H, s),4.10-4.21(1H, m), 4.63(1H, d, J = 5.7 Hz), 6.11-6.17(1H, m),7.29-7.37(6H, m) 354 8

colorless cryst 149.0-150.0 CDCl₃ 1.24-1.35(1H, m), 1.40-1.52(2H, m),1.72- 1.99(5H, m), 2.15-2.23(2H, m), 2.47(3H, s), 4.15- 4.26(1H, m),7.12-7.16(1H, m), 7.35-7.40(2H, m), 7.47(1H, s), 7.49-7.51(3H, m) 340

TABLE 31 Ex- properties am- m.p. (° C.) ple (recryst. MS(FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺  9

colorless cryst. 221.8-224.2 CDCl₃ 1.25-1.53(3H, m), 1.74-1.96(5H, m),1.89(3H, s), 2.19-2.23(2H, m), 2.47(3H, s), 3.26(3H, s), 4.18- 4.23(1H,m), 7.17-7.20(2H, m), 7.49(1H, s), 7.64- 7.67(3H, m) 411 10

colorless cryst. 241.5-242.8 CDCl₃ 1.23-1.33(1H, m), 1.40-1.52(2H, m),1.70- 1.97(5H, m), 2.17-2.23(2H, m), 2.20(3H, s), 2.46(3H, s), 3.93(3H,s), 4.13-4.20(1H, m), 6.73-6.76(1H, m), 7.46(1H, s), 7.59-7.61(1H, m),7.67-7.69(1H, m), 7.77- 7.79(1H, m), 8.30-8.34(1H, m) 427 11

colorless cryst. >270 CDCl₃ 1.23-1.33(1H, m), 1.40-1.52(2H, m), 1.71-1.97(5H, m), 2.15-2.22(2H, m), 2.22(3H, s), 2.46(3H, s), 3.22(2H, t, J =8.5 Hz), 4.08(2H, t, J = 8.5 Hz), 4.13- 4.21(1H, m), 7.05-7.08(1H, m),7.44(1H, s), 7.53- 7.55(1H, m), 7.79(1H, brs), 8.16-8.19(1H, m) 423 12

colorless cryst. 195.9-197.9 CDCl₃ 1.23-1.33(1H, m), 1.31(3H, t, J = 7.1Hz), 1.41- 1.54(2H, m), 1.71-1.95(5H, m), 2.15-2.22(2H, m), 2.46(3H, s),4.15-4.22(1H, m), 4.23(2H, q, J = 7.1 Hz), 6.52(1H, brs), 7.36-7.38(2H,m), 7.45(1H, s), 7.52- 7.55(3H, m) 427

TABLE 32 Ex- properties am- m.p. (° C.) MS ple (recryst. (FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 13

colorless cryst/ 200.3-200.8 CDCl₃ 1.23-1.32(1H, m), 1.39-1.52(2H, m),1.53(9H, s), 1.73-1.95(5H, m), 2.16-2.24(2H, m), 2.46(3H, s), 3.10(2H,t, J = 8.5 Hz), 3.99 (2H, t, J = 8.5 Hz), 4.15-4.22(1H, m), 7.08-7.20(1H, m), 7.44(1H, s), 7.53(1H, brs), 7.58-7.72(1H, m) 481 14

  HCl colorless cryst. 268.3-271.2 DMSO 1.23-1.33(1H, m), 1.40-1.51(2H,m), 1.66-1.90(5H, m), 2.04-2.13(2H, m), 2.40(3H, s), 3.23(2H, t, J = 7.7Hz), 3.74(2H, t, J = 7.7 Hz), 4.29-4.31(1H, m), 7.41-7.45(1H, m), 7.69-7.72(1H, m), 7.90-7.92(1H, m), 8.17(1H, s), 10.49-10.51(1H, m),11.16(1H, brs) 381 15

pale brown cryst. 234.3-235.6 CDCl3 1.23-1.32(1H, m), 1.39-1.52(2H, m),1.72-1.98(5H, m), 2.16-2.23(2H, m), 2.46 (3H, s), 4.13-4.22(1H, m),6.53-6.55(1H, m), 7.21-7.23(1H, m), 7.31-7.38(2H, m), 7.47(1H, s),7.67(1H, brs), 7.89-7.91(1H, m), 8.20(1H, brs) 379 16

pale yellow cryst. 216.9-218.4 CDCl3 1.23-1.32(1H, m), 1.40-1.52(2H, m),1.71-1.88(3H, m), 1.90-1.98(2H, m), 2.15- 2.22(2H, m), 2.46(3H, s),3.12-3.16(4H, m), 3.85-3.88(4H, m), 4.13-4.22(1H, m), 6.90- 6.93(2H, m),7.43(1H, s), 7.47-7.51(3H, m) 424

TABLE 33 Ex- properties am- m.p. (° C.) MS ple (recryst. (FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 17

pale yellow cryst. 193.1-194.8 CDCl₃ 1.23-1.35(1H, m), 1.40-1.52(2H, m),1.72- 1.89(3H, m), 1.90-1.98(2H, m), 2.17-2.23(2H, m), 2.48(3H, s),4.16-4.24(1H, m), 7.51-7.57(2H, m), 7.80(1H, brs), 8.00(1H, dd, J = 1.8and 8.2 Hz), 8.07(1H, dd, J = 1.8 and 8.2 Hz), 8.43(1H, s) 385 18

yellow cryst. 150.0-153.8 CDCl₃ 1.23-1.35(1H, m), 1.39-1.55(2H, m),1.72- 1.98(5H, m), 2.16-2.23(2H, m), 2.46(3H, s), 3.49(2H, brs),4.15-4.24(1H, m), 6.75-6.84(2H, m), 7.06- 7.09(1H, m), 7.43-7.46(2H, m),7.60(1H, brs) 355 19

pale yellow cryst. >270 DMSO 1.20-1.31(1H, m), 1.39-1.51(2H, m), 1.65-1.88(5H, m), 2.01-2.11(2H, m), 2.05(3H, s), 2.40(3H, s), 4.18-4.26(1H,m), 7.21-7.29(2H, m), 7.39-7.42(1H, m), 8.06-8.11(2H, m), 9.93(1H, brs),10.21(1H, brs) 397 20

colorless cryst. >270 (EtOH) DMSO 1.19-1.30(1H, m), 1.37-1.50(2H, m),1.63- 1.87(5H, m), 2.04-2.11(2H, m), 2.40(3H, s), 2.78(3H, d, J = 4.4Hz), 4.16-4.22(1H, m), 7.78-7.85(4H, m), 8.10(1H, s), 8.30-8.32(1H, m),10.38(1H, brs) 397

TABLE 34 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 21

colorless cryst. 223.2-226.5 CDCl₃ 1.25 (3H, t, J = 7.3 Hz) 1.23-1.35(1H, m), 1.39-1.55 (2H, m), 1.72-1.89 (3H, m), 1.90-1.98 (2H, m),2.18-2.24 (2H, m), 2.41-2.49 (2H, m), 2.46 (3H, s), 3.22 (2H, t, J = 8.5Hz), 4.07 (2H, t, J = 8.5 Hz), 4.17-4.25 (1H, m), 7.06- 7.09 (1H, m),7.45 (1H, s), 7.59-7.61 (1H, m), 7.78-7.80 (1H, m), 8.19-8.22 (1H, m)437 22

pale yellow cryst. 155.0-159.0 CDCl₃ 0.88 (3H, t, J = 6.8 Hz), 1.23-1.52(3H, m), 1.73-1.98 (5H, m), 2.17- 2.22 (2H, m), 2.45 (3H, s), 3.13 (2H,t, J = 8.6 Hz), 4.03 (2H, t, J = 8.6 Hz), 4.15-4.23 (1H, m), 4.22- 4.37(2H, m), 7.11-7.18 (1H, m), 7.45 (1H, s), 7.59 (1H, brs), 7.63-7.74 (1H,m), 7.75-7.89 (1H, m) 453 23

colorless cryst. 192.8-196.6 CDCl₃ 1.23 (6H, d, J = 6.7 Hz), 1.23-1.35(1H, m), 1.38-1.52 (2H, m), 1.72- 1.99 (5H, m), 2.17-2.22 (2H, m), 2.46(3H, s), 2.74- 2.83 (1H, m), 3.22 (2H, t, J = 8.4 Hz), 4.09-4.24 (1H,m), 4.15 (2H, t, J = 8.4 Hz), 7.05-7.09 (1H, m), 7.45 (1H, s), 7.59-7.61(1H, m), 7.79- 7.81 (1H, m), 8.22-8.25 (1H, m) 451 24

colorless cryst. 179.9-183.1 CDCl₃ 1.03 (3H, t, J = 7.3 Hz), 1.23-1.35(1H, m), 1.38-1.52 (2H, m), 1.74- 1.99 (7H, m), 2.18-2.24 (2H, m), 2.40(2H, t, J = 7.3 Hz), 2.46 (3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.08 (2H,t, J = 8.5 Hz), 4.12- 4.27 (1H, m), 7.06-7.09 (1H, m), 7.45 (1H, s),7.59- 7.61 (1H, m), 7.79-7.81 (1H, m), 8.20-8.23 (1H, m) 451

TABLE 35 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 25

colorless cryst. 162.8-167.3 CDCl₃ 1.21-1.51 (3H, m), 1.38 (9H, s),1.72-1.99 (5H, m), 2.18-2.22 (2H, m), 2.45 (3H, s), 3.15 (2H, t, J = 8.1Hz), 4.12-4.27 (1H, m), 4.25 (2H, t, J = 8.1 Hz), 7.08 (1H, dd, J = 2.1and 8.7 Hz), 7.45 (1H, s), 7.62-7.65 (1H, m), 7.79-7.81 (1H, m),8.19-8.22 (1H, m) 465 26

pale yellow cryst. 171.8-176.3 CDCl₃ 1.22-1.37 (1H, m), 1.39-1.52 (2H,m), 1.72-1.89 (3H, m), 1.90-1.99 (2H, m), 2.18-2.24 (2H, m), 2.46 (3H,s), 3.56 (2H, s), 4.14-4.22 (1H, m), 6.81-6.84 (1H, m), 7.28-7.31 (1H,m), 7.46 (1H, s), 7.50-7.52 (1H, m), 7.55- 7.58 (1H, m), 7.62-7.64 (1Hm) 395 27

vcolorless cryst. >270 EtOH DMSO 1.19-1.30 (1H, m), 1.37-1.50 (2H, m),1.63-1.88 (5H, m), 2.04-2.11 (2H, m), 2.08 (3H, s), 2.40 (3H, s),4.19-4.28 (1H, m), 7.60-7.65 (2H, m), 7.96-7.98 (1H, m), 8.06 (1H, s),9.49 (1H, brs), 10.36 (1H, brs) 431 28

colorless cryst. 262.2-263.8 EtOH DMSO 1.12 (3H, t, J = 7.2 Hz),1.21-1.30 (1H, m), 1.38- 1.50 (2H, m), 1.63-1.88 (5H, m), 2.04-2.11 (2H,m), 2.40 (3H, s), 3.23-3.32 (2H, m), 4.19-4.28 (1H, m), 7.78-7.86 (4H,m), 8.11 (1H, s), 8.35- 8.36 (1H, m), 10.46 (1H, brs) 411

TABLE 36 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 29

pale yellow cryst. 135.2-136.3 CDCl₃ 1.22-1.35 (1H, m), 1.39-1.52 (2H,m), 1.72- 1.98 (5H, m), 2.16-2.22 (2H, m), 2.46 (3H, s), 3.39 (3H, s),4.14-4.22 (1H, m), 4.44 (2H, s), 7.33-7.36 (2H, m), 7.47 (1H, s),7.57-7.60 (3H, m) 384 30

pale yellow cryst. 190.0-191.9 CDCl₃ 1.22-1.35 (1H, m), 1.39-1.51 (2H,m), 1.72- 1.98 (5H, m), 2.17-2.22 (2H, m), 2.47 (3H, s), 4.12-4.22 (1H,m), 4.68 (2H, d, J = 5.1 Hz), 7.35- 7.39 (2H, m), 7.48 (1H, s),7.58-7.61 (2H, m), 7.64 (1H, brs) 370 31

colorless cryst. 246.5-248.3 CDCl₃ 1.22-1.35 (1H, m), 1.39-1.51 (2H, m),1.72- 1.89 (3H, m), 1.90-1.98 (2H, m), 2.17-2.22 (2H, m), 2.47 (3H, s),3.39- 3.89 (8H, m), 4.13-4.25 (1H, m), 7.40-7.43 (2H, m), 7.55 (1H, s),7.61- 7.64 (2H, m), 7.85 (1H, brs) 453 32

colorless cryst. 193.2-196.0 CDCl₃ 1.22-1.34 (1H, m), 1.39-1.51 (2H, m),1.72- 1.89 (3H, m), 1.90-1.98 (2H, m), 2.16-2.25 (2H, m), 2.38-2.56 (4H,m), 2.36 (3H, s), 2.47 (3H, s), 3.36- 3.90 (4H, m), 4.15-4.25 (1H, m),7.39-7.42 (2H, m), 7.56 (1H, s), 7.59-7.62 (2H, m), 7.91 (1H, brs) 466

TABLE 37 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 33

colorless cryst. 240.0-243.1 EtOH DMSO 1.17-1.30 (1H, m), 1.38-1.50 (2H,m), 1.62- 1.88 (5H, m), 2.03-2.11 (2H, m), 2.40 (3H, s), 2.95 (3H, s),4.17-4.25 (1H, m), 7.18-7.21 (2H, m), 7.66- 7.69 (2H, m), 8.05 (1H, s),9.60 (1H, brs), 10.23 (1H, brs) 433 34

pale yellow cryst. 338.7-240.0 AcOEt/ hexane CDCl₃ 1.20-1.31 (1H, m),1.39-1.50 (2H, m), 1.63- 1.89 (5H, m), 2.03-2.12 (2H, m), 2.41 (3H, s),2.42 (3H, s), 4.19-4.29 (1H, m), 7.31-7.36 (1H, m), 7.75-7.78 (2H, m),7.93-7.96 (2H, m), 8.13 (1H, s), 10.55 (1H, brs) 433 35

colorless cryst. 203.9-207.1 EtOH DMSO 1.18-1.31 (1H, m), 1.36-1.51 (2H,m), 1.61- 1.89 (5H, m), 2.00-2.11 (2H, m), 2.03 (3H, s), 2.39 (3H, s),3.22 (2H, t, J = 8.0 Hz), 4.15-4.26 (1H, m), 4.49 (2H, t, J = 8.0 Hz),7.28-7.31 (1H, m), 7.60-7.62 (1H, m), 7.79 (1H, s), 7.95-7.98 (1H, m),9.91 (1H, brs) 423 36

colorless cryst. 223.5-225.0 CDCl₃ 1.21-1.38 (1H, m), 1.41-1.55 (2H, m),1.73- 1.91 (3H, m), 1.91-2.00 (2H, m), 2.16-2.25 (2H, m), 2.27 (3H, s),2.42- 2.55 (4H, m), 3.00-3.12 (4H, m), 4.16-4.25 (1H, m), 7.52 (1H, s),7.73- 7.80 (5H, m) 502

TABLE 38 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 37

colorless cryst. 203.2-205.8 CDCl₃ 1.22-1.38 (1H, m), 1.40-1.53 (2H, m),1.72- 1.90 (3H, m), 1.91-1.99 (2H, m), 2.16-2.22 (2H, m), 2.40 (3H, s),3.40 (3H, s), 3.55-3.60 (2H, m), 3.64-3.69 (2H, m), 4.15-4.25 (1H, m),6.48- 6.52 (1H, m), 7.52 (1H, s), 7.67-7.71 (2H, m), 7.78-7.81 (2H, m),7.83 (1H, brs) 441 38

colorless cryst. 177.8-179.4 CDCl₃ 1.22-1.36 (1H, m), 1.40-1.53 (2H, m),1.72- 1.89 (3H, m), 1.91-1.99 (2H, m), 2.16-2.23 (2H, m), 2.47 (3H, s),2.60 (3H, s), 4.15-4.25 (1H, m), 7.51 (1H, s), 7.71-7.74 (2H, m), 7.78(1H, brs), 7.97-8.01 (2H, m) 382 39

colorless cryst. 239.0-243.8 CDCl₃ 1.22-1.36 (1H, m), 1.40-1.52 (2H, m),l.72- 1.89 (3H, m), 1.90-1.99 (2H, m), 2.17-2.24 (2H, m), 2.47 (3H, s),3.02 (3H, brs), 3.12 (3H, brs), 4.15-4.25 (1H, m), 7.37 (2H, dd, J = 1.8and 8.5 Hz), 7.55 (2H, dd, J = 1.8 and 8.5 Hz), 7.64 (1H, s), 8.17 (1H,brs) 411 40

colorless cryst. 159.5-163.3 CDCl₃ 1.22-1.36 (1H, m), 1.40 (3H, t, J =7.1 Hz), 1.40-1.52 (2H, m), 1.72- 1.89 (3H, m), 1.90-1.99 (2H, m),2.17-2.24 (2H, m), 2.47 (3H, s), 4.15- 4.25 (1H, m), 4.37 (2H, q, J =7.1 Hz), 7.50 (1H, s), 7.68-7.71 (2H, m), 7.74 (1H, brs), 8.04- 8.08(2H, m) 412

TABLE 39 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 41

colorless cryst. 265.9-268.8 DMSO 1.18-1.31 (1H, m), 1.39-1.51 (2H, m),1.62- 1.89 (5H, m), 2.04-2.11 (2H, m), 2.41 (3H, s), 4.18- 4.26 (1H, m),7.84-7.87 (2H, m), 7.92-7.95 (2H, m), 8.13 (1H, s), 10.48 (1H, brs) 38442

colorless cryst. 215.8-216.8 CDCl₃ 1.22-1.38 (1H, m), 1.40-1.52 (2H, m),1.72- 1.89 (3H, m), 1.90-1.99 (2H, m), 2.18-2.24 (2H, m), 2.50 (3H, s),4.09 (3H, s), 4.15-4.25 (1H, m), 7.50 (1H, s), 7.81 (1H, d, J = 2.3 Hz),7.97 (1H, dd, J = 2.3 and 9.0 Hz), 8.54 (1H, brs), 8.65 (1H, d, J = 9.0Hz) 415 43

yellow cryst. 102.2-105.0 CDCl₃ 1.22-1.37 (1H, m), 1.39-1.52 (2H, m),1.70- 1.98 (5H, m), 2.17-2.23 (2H, m), 2.47 (3H, s), 3.62 (2H, brs),3.90 (3H, s), 4.13- 4.24 (1H, m), 6.30-6.35 (2H, m), 7.40 (1H, s), 8.06(1H, brs), 8.12-8.15 (1H, m) 384 (M+) 44

pale yellow cryst. 263.1-265.3 EtOH DMSO 1.18-1.31 (1H, m), 1.38-1.51(2H, m), 1.63- 1.88 (5H, m), 2.04-2.11 (2H, m), 2.05 (3H, s), 2.38 (3H,s), 3.79 (3H, s), 4.15-4.29 (1H, m), 7.08-7.11 (1H, m), 7.45- 7.51 (2H,m), 8.02 (1H, s), 9.45 (1H, brs), 9.37 (1H, brs) 427

TABLE 40 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 45

colorless cryst. 255.7-259.5 EtOH DMSO 1.16 (6H, d, J = 6.6 Hz), 1.18-1.31 (1H, m), 1.38- 1.51 (2H, m), 1.63- 1.88 (5H, m), 2.03- 2.12 (2H,m), 2.41 (3H, s), 4.04-4.15 (1H, m), 4.19-4.28 (1H, m), 7.78-7.81 (2H,m), 7.84-7.87 (2H, m), 8.09 (1H, d, J = 7.4 Hz), 8.11 (1H, s), 10.39(1H, brs) 425 46

colorless cryst. 194.2-196.0 DMSO 1.20-1.33 (1H, m), 1.39-1.54 (2H, m),1.65-1.95 (5H, m), 2.05-2.15 (2H, m), 2.41 (3H, s), 3.26- 3.40 (2H, m),3.49- 3.59 (2H, m), 4.18- 4.29 (1H, m), 4.69- 4.73 (1H, m), 7.79- 7.88(4H, m), 8.11 (1H, s), 8.31-8.35 (1H, m), 10.40 (1H, brs) 427 47

colorless cryst. >270 EtOH DMSO 1.19-1.33 (1H, m), 1.39-1.52 (2H, m),1.63-1.90 (5H, m), 2.05- 2.12 (2H, m), 2.08 (3H, s), 2.40 (3H, s), 4.18-4.28 (1H, m), 8.01-8.08 (2H, m), 8.04 (1H, s), 8.65-8.67 (1H, m), 10.36(1H, brs), 10.45 (1H, brs) 398 48

colorless cryst. 133.5-136.0 CDCl₃ 1.22-1.37 (1H, m), 1.39-1.52 (2H, m),1.71-1.98 (5H, m), 2.16-2.23 (2H, m), 2.46 (3H, s), 3.81 (3H, s),4.13-4.25 (1H, m), 6.91 (2H, dd, J = 2.1 and 6.9 Hz), 7.44 (1H, s), 7.49(2H, dd, J = 2.1 and 6.9 Hz), 10.51 (1H, brs) 370

TABLE 41 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 49

colorless cryst. 161.0-164.2 CDCl₃ 1.22-1.35 (1H, m), 1.39-1.54 (4H, m),1.61- l.98 (9H, m), 2.04-2.21 (4H, m), 2.43 (3H, s), 4.13-4.22 (1H, m),4.31- 4.42 (1H, m), 5.80 (1H, d, J = 6.6 Hz), 7.29 (1H, s) 332 50

colorless cryst. 184.0-185.8 CDCl₃ 1.15-1.35 (4H, m), 1.37-1.52 (4H, m),1.61- 1.70 (1H, m), 1.71-1.98 (7H, m), 2.00-2.09 (2H, m), 2.14-2.21 (2H,m), 2.43 (3H, s), 3.88-3.98 (1H, m), 4.13-4.22 (1H, m), 5.73 (1H, d, J =8.0 Hz), 7.30 (1H, s) 346 51

colorless cryst. 256.0-257.3 CDCl₃ 1.21-1.37 (1H, m), 1.40-1.52 (2H, m),1.48 (9H, s), 1.71-1.89 (3H, m), 1.91-1.99 (2H, m), 2.18- 2.25 (2H, m),2.46 (3H, s), 4.15-4.22 (1H, m), 5.92 (1H, brs), 7.53 (1H, s), 7.63-7.66(2H, m), 7.70- 7.73 (2H, m), 7.85 (1H, brs) 439 52

colorless cryst. >270 CDCl₃ 1.21-1.36 (1H, m), 1.29 (6H, d, J = 6.6 Hz),1.40-1.52 (2H, m), 1.71- 1.89 (3H, m), 1.91-1.99 (2H, m), 2.18-2.24 (2H,m), 2.47 (3H, s), 4.15- 4.24 (1H, m), 4.28-4.35 (1H, m), 5.85 (1H, d, J= 7.6 Hz), 7.57 (1H, s), 8.08 (1H, dd, J = 2.2 and 8.7 Hz), 8.36 (1H, d,J = 8.7 Hz), 8.56 (1H, brs), 8.71-8.72 (1H, m) 426

TABLE 42 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 53

pale brown cryst. 216.9-218.5 EtOH/Et₂O DMSO 1.19-1.31 (1H, m),1.39-1.52 (2H, m), 1.63-1.89 (5H, m), 2.05-2.11 (2H, m), 2.39 (3H, s),4.18-4.27 (1H, m), 7.54-7.58 (2H, m), 7.64- 7.68 (2H, m), 8.04 (1H, s),8.24 (1H, brs), 10.14 (1H, brs), 10.21 (1H, brs) 383 54

colorless cryst. 226.0-227.8 CDCl₃ 1.21-1.36 (1H, m), 1.41 (9H, s),1.40-1.52 (2H, m), 1.71-1.89 (3H, m), 1.91-1.99 (2H, m), 2.18-2.25 (2H,m), 2.46 (3H, s), 2.97-3.01 (4H, m), 3.50-3.55 (4H, m), 4.18- 4.27 (1H,m), 7.53 (1H, s), 7.73-7.76 (2H, m), 7.78- 7.81 (2H, m), 7.82 (1H, brs)588 55

colorless cryst. >270 DMSO 1.19-1.31 (1H, m), 1.39-1.50 (2H, m), 1.63-1.89 (5H, m), 2.05-2.11 (2H, m), 2.41 (3H, s), 3.09- 3.22 (8H, m),4.19-4.30 (1H, m), 7.77-7.80 (2H, m), 8.05-8.08 (2H, m), 8.22 (1H, s),8.84 (1H, brs), 10.74 (1H, brs) 488 56

colorless cryst. >270 CDCl₃ 1.21-1.35 (1H, m), 1.39-1.51 (2H, m), 1.74-1.99 (5H, m), 2.17-2.26 (2H, m), 2.48 (3H, s), 3.00- 3.03 (4H, m),3.72-3.77 (4H, m), 4.18-4.26 (1H, m), 7.53 (1H, s), 7.71-7.83 (5H, m)489

TABLE 43 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 57

colorless cryst. >270 CDCl₃ 1.21-1.35 (1H, m), 1.37-1.51 (2H, m), 1.73-1.99 (5H, m), 2.17-2.26 (2H, m), 2.48 (3H, s), 3.06 (3H, s), 4.14-4.26(1H, m), 7.54 (1H, s), 7.81-7.84 (3H, m), 7.93- 7.96 (2H, m) 418 58

colorless cryst. 217.7-219.9 EtOH DMSO 0.80-0.91 (4H, m), 1.15-1.30 (1H,m), 1.39- 1.50 (2H, m), 1.63-1.88 (5H, m), 1.90-1.99 (1H, m), 2.02-2.10(2H, m), 2.39 (3H, s), 3.15-3.22 (2H, m), 4.18-4.35 (3H, m), 7.38-7.41(1H, m), 7.67-7.69 (1H, m), 7.94- 7.99 (1H, m), 8.03 (1H, s), 10.16 (1H,brs) 449 59

colorless cryst. 132.8-137.4 CDCl₃ 1.21-1.37 (1H, m), 1.39-1.53 (2H, m),1.72- 1.98 (5H, m), 2.17-2.23 (2H, m), 2.47 (3H, s), 2.86 (3H, s), 3.18(2H, t, J = 8.4 Hz), 4.01 (2H, t, J = 8.4 Hz), 4.15-4.27 (1H, m),7.14-7.18 (1H, m), 7.37-7.40 (1H, m), 7.47 (1H, s), 7.58 (1H, brs), 7.74(1H, brs) 459 60

colorless cryst. 213.1-217.5 CDCl₃ 1.22-1.36 (1H, m), 1.40-1.52 (2H, m),1.72- 1.98 (5H, m), 2.18-2.23 (2H, m), 2.47 (3H, s), 2.64 (3H, s),4.15-4.27 (1H, m), 6.63-6.64 (1H, m), 7.29 (1H, dd, J = 1.8 and 8.9 Hz),7.42-7.44 (1H, m), 7.50 (1H, s), 7.75 (1H, brs), 8.10 (1H, d, J = 1.8Hz), 8.38-8.42 (1H, m) 421

TABLE 44 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 61

colorless cryst. 178.9-181.5 CDCl₃ 0.60-0.64 (2H, m), 0.82-0.89 (2H, m),1.21- 1.32 (1H, m), 1.38-1.50 (2H, m), 1.72-1.88 (3H, m), 1.89-1.95 (2H,m), 2.13- 2.20 (2H, m), 2.42 (3H, s), 2.85-2.91 (1H, m), 4.12- 4.20 (1H,m), 6.02 (1H, brs), 7.29 (1H, s) 304 62

colorless cryst. 170.2-172.2 CDCl₃ 1.21-1.50 (5H, m), 1.70-1.95 (5H, m),1.98- 2.04 (2H, m), 2.12-2.23 (4H, m), 2.43 (3H, s), 2.84-2.90 (2H, m),3.52 (2H, s), 3.91-4.02 (1H, m), 4.12-4.21 (1H, m), 5.73 (1H, d, J = 7.2Hz), 7.26-7.33 (6H, m) 437 63

colorless cryst. 164.1-167.3 DMSO 1.17-1.30 (1H, m), 1.39-1.50 (2H, m),1.64- 1.87 (7H, m), 1.92-2.00 (2H, m), 2.02-2.10 (2H, m), 2.36 (3H, s),2.95- 3.01 (2H, m), 3.29-3.36 (2H, m), 3.96-4.05 (1H, m), 4.15-4.22 (1H,m), 7.88 (1H, s), 8.51(1H, d, J = 7.5 Hz), 8.72 (1H, brs) 347 64

colorless cryst. 249.2-250.8 CDCl₃ 1.21-1.50 (5H, m), 1.71-1.88 (3H, m),1.89- 1.98 (2H, m), 2.01-2.07 (1H, m), 2.12 (3H, s), 2.14- 2.21 (3H, m),2.44 (3H, s), 2.72-2.80 (1H, m), 3.18- 3.25 (1H, m), 3.79-3.88 (1H, m),4.12-4.21 (2H, m), 4.59-4.66 (1H, m), 5.78 (1H, d, J = 7.7 Hz), 7.34(1H, s) 389

TABLE 45 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 65

colorless cryst. 137.1-138.1 CDCl₃ 1.25-1.34 (1H, m), 1.31 (3H, t, J =7.1 Hz), 1.38-1.50 (2H, m), 1.71- 1.88 (3H, m), 1.89-1.98 (2H, m),2.16-2.22 (2H, m), 2.46 (3H, s), 4.15- 4.22 (1H, m), 4.28 (2H, q, J =7.1 Hz), 4.62 (2H, s), 6.90-6.94 (2H, m), 7.45(1H, s), 7.49-7.53 (2H,m), 7.55 (1H, brs) 442 66

colorless cryst. 181.0-182.6 DMSO 1.18-1.30 (1H, m), 1.38-1.50 (2H, m),1.64- 1.90 (5H, m), 2.04-2.10 (2H, m), 2.39 (3H, s), 4.18- 4.27 (1H, m),4.64 (2H, s), 6.89-6.92 (2H, m), 7.59- 7.62 (2H, m), 8.01 (1H, s), 10.13(1H, brs) 414 67

colorless cryst. 233.2-235.0 CDCl₃ 1.25-1.35 (1H, m), 1.40-1.52 (2H, m),1.72- 1.98 (5H, m), 2.18-2.23 (2H, m), 2.46 (3H, s), 2.92 (3H, d, J =5.0 Hz), 4.15- 4.24 (1H, m), 4.49 (2H, s), 6.53-6.63 (1H, m), 6.92 (2H,dd, J = 2.1 and 6.9 Hz), 7.47 (1H, s), 7.53 (2H, dd, J = 2.1 and 6.9Hz), 7.57 (1H, brs) 427 68

colorless cryst. 149.3-151.2 CDCl₃ 1.22-1.35 (1H, m), 1.26 (3H, t, J =7.2 Hz), 1.38-1.53 (2H, m), 1.71- 1.98 (5H, m), 2.15-2.22 (2H, m), 2.47(3H, s), 3.60 (2H, s), 4.15-4.22 (1H, m), 4.16 (2H, q, J = 7.2 Hz),7.27-7.30 (2H, m), 7.46 (1H, s), 7.54-7.57 (2H, m), 7.58 (1H, brs) 426

TABLE 46 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 69

colorless cryst. 233.2-234.7 DMSO 1.18-1.30 (1H, m), 1.38-1.51 (2H, m),1.61-1.89 (5H, m), 2.05-2.11 (2H, m), 2.40 (3H, s), 3.53 (2H, s),4.18-4.29 (1H, m), 7.21- 7.25 (2H, m), 7.63-7.66 (2H, m), 8.06 (1H, s),10.20 (1H, brs) 398 70

colorless cryst. 257.3-258.8 DMSO 1.18-1.32 (1H, m), 1.37-1.50 (2H, m),1.61- 1.89 (5H, m), 2.05-2.09 (2H, m), 2.39 (3H, s), 2.57 (3H, d, J =4.6 Hz), 3.35 (2H, s), 4.19-4.27 (1H, m), 7.20-7.23 (2H, m), 7.61- 7.64(2H, m), 7.88-7.91 (1H, m), 8.06 (1H, s), 10.18 (1H, brs) 411 71

colorless cryst. 228.3-229.6 CDCl₃ 1.24-1.35 (1H, m), 1.38-1.52 (2H, m),1.49 (9H, s), 1.72-1.98 (5H, m), 2.15-2.21 (2H, m), 2.46 (3H, s),3.09-3.12 (4H, m), 3.58-3.61 (4H, m), 4.12-4.25 (1H, m), 6.91-6.94 (2H,m), 7.44 (1H, s), 7.47-7.50 (2H, m), 7.53 (1H, brs) 523 72

colorless cryst. 248.5-252.6 DMSO 1.19-1.31 (1H, m), 1.38-1.51 (2H, m),1.63-1.89 (5H, m), 2.04-2.10 (2H, m), 2.39 (3H, s), 3.19-3.22 (4H, m),3.30-3.33 (4H, m), 4.05- 4.15 (1H, m), 6.98-7.01 (2H, m), 7.61-7.64 (2H,m), 8.07 (1H, s), 9.08-9.15 (2H, m), 10.17 (1H, brs) 424

TABLE 47 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 73

colorless cryst. >270 EtOH DMSO 1.18-1.32 (1H, m), 1.35-1.51 (2H, m),1.65- 1.90 (5H, m), 2.04 (3H, s), 2.05-2.11 (2H, m), 2.39 (3H, s),3.02-3.13 (4H, m), 3.55-3.60 (4H, m), 4.15- 4.28 (1H, m), 6.94-6.98 (2H,m), 7.56-7.59 (2H, m), 8.01 (1H, s), 10.07 (1H, brs) 466 74

colorless cryst. 181.3-182.8 CDCl₃ 1.22-1.52 (7H, m), 1.72-1.88 (3H, m),1.89- 1.98 (2H, m), 2.00-2.08 (2H, m), 2.10-2.22 (4H, m), 2.43 (3H, s),3.60- 3.71 (1H, m), 3.90-4.00 (1H, m), 4.12-4.21 (1H, m), 5.68 (1H, d, J= 7.8 Hz), 7.30 (1H, s) 362 75

colorless cryst. 177.2-178.5 CDCl₃ 1.21-1.35 (1H, m), 1.39-1.50 (2H, m),1.72- 1.88 (5H, m), 1.90-1.98 (2H, m), 2.15-2.23 (2H, m), 2.32-2.60 (6H,m), 2.43 (3H, s), 4.14-4.22 (1H, m), 4.40-4.50 (1H, m), 5.86 (1H, d, J =7.6 Hz), 7.35 (1H, s) 360 76

colorless cryst. 117.2-121.2 CDCl₃ 1.21-1.35 (1H, m), 1.40-1.52 (2H, m),1.72- 1.89 (3H, m), 1.90-1.98 (2H, m), 2.16-2.22 (2H, m), 2.30 (3H, s),2.34- 2.42 (4H, m), 2.46 (3H, s), 3.59-3.68 (4H, m), 4.14-4.25 (1H, m),4.68 (2H, s), 6.93-6.97 (2H, m), 7.46 (1H, s), 7.49- 7.52 (2H, m), 7.60(1H, brs) 496

TABLE 48 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 77

colorless cryst. 178.2-180.8 CDCl₃ 1.22-1.35 (1H, m), 1.37-1.52 (2H, m),1.72- 1.89 (3H, m), 1.90-1.98 (2H, m), 2.15-2.22 (2H, m), 2.46 (3H, s),2.99 (3H, s), 3.10 (3H, s), 4.15-4.23 (1H, m), 4.69 (2H, s), 6.94-6.98(2H, m), 7.46 (1H, s), 7.48- 7.51 (2H, m), 7.56 (1H, brs) 441 78

colorless cryst. 202.2-203.8 CDCl₃ 1.22-1.35 (1H, m), 1.40-1.52 (2H, m),1.72- 1.89 (3H, m), 1.91-1.99 (2H, m), 2.03 (3H, s), 2.19-2.25 (2H, m),2.48 (3H, s), 2.59-2.64 (6H, m), 3.02-3.08 (4H, m), 4.13 (2H, t, J = 5.7Hz), 4.15-4.26 (1H, m), 7.53 (1H, s), 7.73-7.81 (4H, m), 7.84 (1H, brs)574 79

colorless cryst. 141.4-145.8 CDCl₃ 1.22-1.35 (1H, m), 1.39-1.53 (2H, m),1.72- 1.98 (5H, m), 2.18-2.22 (2H, m), 2.34 (1H, brs), 2.48 (3H, s),2.52-2.58 (2H, m), 2.60-2.63 (4H, m), 3.03-3.09 (4H, m), 3.58-3.61 (2H,m), 4.17- 4.26 (1H, m), 7.54 (1H, s), 7.74-7.82 (4H, m), 7.84 (1H, brs)532 80

colorless cryst. >270 EtOH DMSO 1.17-1.50 (7H, m), 1.63-1.90 (9H, m),1.78 (3H, s), 2.00-2.08 (2H, m), 2.35 (3H, s), 3.41-3.57 (1H, m),3.60-3.72 (1H, m), 4.12-4.24 (1H, m), 7.73 (1H, d, J = 7.6 Hz), 7.79(1H, s), 8.24 (1H, d, J = 7.7 Hz) 403

TABLE 49 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 81

colorless cryst. 217.5-218.3 CDCl₃ 1.21-1.32(1H, m), 1.37-1.51(2H, m),1.70- 1.88(3H, m), 1.89-1.97(2H, m), 2.13-2.21(2H, m), 2.43(3H, s),3.00(3H, d, J = 4.9 Hz), 4.10-4.21(1H, m), 5.85-5.93(1H, m), 7.30(1H, s)278 82

colorless cryst. 125.1-127.8 CDCl₃ 1.54-1.69(2H, m), 1.75-1.93(6H, m),2.09(3H, s), 3.19(2H, s), 4.61-4.60(1H, m) 167 83

browm oil CDCl₃ 1.60-1.72(2H, m), 1.86-1.98(2H, m), 2.00- 2.10(4H, m),2.23(3H, s), 4.68-4.75(1H, m), 5.95(1H, s) 84

colorless oil CDCl₃ 1.65-1.75(2H, m), 1.92-2.02(2H, m), 2.14- 2.13(4H,m), 2.45(3H, s), 4.72-4.80(1H, m), 9.85(1H, s) 213

TABLE 50 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 85

colorless oil CDCl₃ 1.20(3H, t, J = 7.1 Hz), 1.65-1.75(2H, m), 1.92-2.11(6H, m), 2.48(3H, s), 3.58(2H, s), 4.10(2H, q, J = 7.1 Hz),5.17-5.22 (1H, m), 10.01(1H, s) 297 86

colorless oil CDCl₃ 1.38(3H, t, J = 7.1 Hz), 1.68-1.78(2H, m), 1.83-1.95(2H, m), 2.05-2.24(4H, m), 2.44(3H, s), 4.35(2H, q, J = 7.1 Hz),4.66-4.72 (1H, m), 7.69(1H, s) 279 87

colorless cryst. 167.5-168.9 CDCl₃ 1.68-1.80(2H, m), 1.84-1.96(2H, m),2.08- 2.25(4H, m), 2.47(3H, s), 4.66-4.75(1H, m), 7.80(1H, s) 251 88

colorless cryst. >270 EtOH DMSO 1.62-1.72(2H, m), 1.75-1.85(2H, m),1.94- 2.04(2H, m), 2.02(3H, s), 2.09-2.19(2H, m), 2.40(3H, s),4.70-4.79(1H, m), 7.52-7.55 (2H, m), 7.60-7.63(2H, m), 8.03(1H, s),9.88(1H, brs), 10.16(1H, brs) 383

TABLE 51 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 89

pale yellow cryst. 134.0-137.7 CDCl₃ 1.45-1.71(6H, m), 1.72-1.97(6H, m),2.09(3H, s), 3.18(2H, s), 4.15-4.21(1H, m). 195 90

brown oil CDCl₃ 1.48-1.72(6H, m), 1.78-1.88(2H, m), 1.91- 2.00(2H, m),2.01-2.11(2H, m), 2.23(3H, s), 4.30- 4.38(1H, m), 5.93(1H, s) 91

colorless cryst. 75.0-76.3 CDCl₃ 1.50-1.73(6H, m), 1.81-1.91(2H, m),1.93- 2.02(2H, m), 2.03-2.14(2H, m), 2.45(3H, s), 4.39- 4.46(1H, m),9.67(1H, s) 241 92

colorless oil CDCl₃ 1.38(3H, t, J = 7.1 Hz), 1.51-1.73(6H, m), 1.79-1.89(2H, m), 1.99-2.10(2H, m), 2.15-2.23(2H, m), 2.44(3H, s), 4.35(2H,q, J = 7.1 Hz), 4.32-4.42(1H, m), 7.69(1H, s) 307

TABLE 52 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 93

colorless cryst. 239.8-241.4 CDCl₃ 1.52-1.75(6H, m), 1.80-1.90(2H, m),2.00- 2.10(2H, m), 2.16-2.25 (2H, m), 2.46(3H, s), 4.35- 4.41(1H, m),7.79(1H, s) 279 94

colorless cryst. >270 EtOH DMSO-d₆ 1.50-1.82(8H, m), 1.88-2.12(4H, m),1.97(3H, s), 2.39(3H, s), 4.32-4.46(1H, m), 7.52- 7.55(2H, m),7.60-7.63(2H, m), 8.03(1H, s), 9.88(1H, brs), 10.15(1H, brs) 411 95

colorless cryst. 157-159 CDCl₃ 1.18-1.45(3H, m), 1.63-1.82(3H, m), 1.84-1.93(2H, m), 2.04-2.13(2H, m), 2.21(3H, s), 3.45(3H, s), 4.04-4.14(1H,m), 6.11(1H, s), 7.27-7.33(2H. m), 7.39- 7.49(3H, m) 354 96

colorless cyrst. 223-224 CDCl₃ 1.22-1.36(1H, m), 1.40-1.53(2H, m), 1.72-1.89(3H m), 1.91-2.00(2H, m), 2.15-2.25(2H, m), 2.47(3H, s),4.15-4.25(1H, m), 7.53(1H, s), 7.54- 7.58(2H, m), 7.74(1H, brs),8.53-8.58(2H, m) 341

TABLE 53 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺  97

colorless solid 178-180 CDCl₃ 1.23-1.35(1H, m), 1.39-1.42(2H, m), 1.72-1.89(3H, m), 1.90-1.97 (2H, m), 2.16-2.25(2H, m), 2.48(3H, s), 4.15-4.25(1H, m), 7.29-7.35(1H, m), 7.53(1H, s), 7.68(1H, brs), 8.24-8.29(1H, m),8.38- 8.42(1H, m), 8.63-8.66(1H, m) 341  98

pale yellow cryst. 210-212 CDCl₃ 1.22-1.52(3H, m), 1.72-1.89(3H, m),1.91- 1.98(2H, m), 2.17-2.26 (2H, m), 2.48(3H, s), 4.15- 4.25(1H, m),7.54(1H, s), 7.77-7.81(2H, m), 7.87(1H, brs), 8.24-2.29(2H, m) 385  99

pale yellow foamy solid CDCl₃ 1.22-1.34(1H, m), 1.38-1.51(2H, m), 1.71-1.98(5H, m), 2.14-2.23 (2H, m), 2.45(3H, s), 4.14- 4.24(1H, m),6.85-6.72 (2H, m), 7.33-7.38(2H, m), 7.42(1H, s), 7.48(1H, s) 355 100

colorless solid >300 CDCl₃ 1.19-1.30(1H, m), 1.36-1.50(2H, m), 1.63-1.86(5H, m), 2.03(3H, s), 2.03-2.10(2H, m), 2.39(3H, s), 4.15-4.26(1H,m), 7.51-7.56 (2H, m), 7.59-7.64(2H, m), 8.04(1H, s), 9.91(1H, brs),10.18(1H, brs) 397

TABLE 54 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 101

pale yellow cryst. 233-236 CDCl₃ 1.23-1.35(1H, m), 1.38-1.54(2H, m),1.72- 1.97(5H, m), 2.15-2.24(2H, m), 2.47(3H, s), 3.52(3H, s), 4.03(2H,s), 4.15-4.25 (1H, m), 7.47(1H, s), 7.56- 7.65(4H, m), 8.25(1H, brs) 427102

colorless solid 120-123 CDCl₃ 1.23-1.36(1H, m), 1.39-1.52(2H, m), 1.72-1.98(5H, m), 2.18-2.24(2H, m), 2.48(3H, s), 4.01 (3H, s), 4.15-4.25(1H,m), 7.58(1H, s), 7.88(1H, brs), 8.18(1H, d, J = 8.6 Hz), 8.51(1H, dd, J= 2.6 and 8.6 Hz), 8.71(1H, d, J = 2.6 Hz) 399 103

pale yellow solid 161-166 DMSO-d₆ 1.18-1.42(1H, m), 1.38-1.51(2H, m),1.65- 1.89(5H, m), 2.05-2.13 (2H, m), 2.42(3H, s), 4.19- 4.28(1H, m),8.07(1H, d, J = 8.6 Hz), 8.14(1H, s), 8.35(1H, dd, J = 2.4 and 8.6 Hz),8.99(1H, d, J = 2.4 Hz), 10.71(1H, brs) 385 104

colorless solid 255-257 CDCl₃ 1.21-1.35(1H, m), 1.40-1.60(2H, m), 1.72-1.97(5H, m), 2.16-2.25(2H, m), 2.47(3H, s), 3.04(3H, d, J = 5.1 Hz),4.15-4.25(1H, m), 7.55(1H, s), 7.79(1H, brs), 7.86-7.92(2H, m), 8.21-8.24(2H, m), 8.76(1H, brs) 398

TABLE 55 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 105

colorless cryst. 243-245 CDCl₃ 1.23-1.35(1H, m), 1.39-1.52(2H, m), 1.72-1.98(5H, m), 2.16-2.24(2H, m), 2.48(3H, s), 3.11(3H, s), 3.17(3H, s),4.15-4.25(1H, m), 7.51(1H, d, J = 8.5 Hz), 7.78(1H, s), 8.00(1H, dd, J =2.5 and 8.5 Hz), 8.57 8.60(2H, m) 412 106

yellow solid 206-208 CDCl₃ 1.22-1.35(1H, m), 1.38-1.50(2H, m), 1.70-1.97(5H, m), 2.15-2.23(2H, m), 2.36(3H, s), 2.46(3H, s), 2.56-2.63(4H,m), 3.17-3.23 (4H, m), 4.14-4.23(1H, m), 6.93(2H, d, J = 8.9 Hz), 7.44(1H, s), 7.47(2H, d, J = 8.9 Hz), 7.53(1H, brs) 438 107

colorless cryst. 175(dec.) (MeOH) D₂O 1.05-1.18(1H, m), 1.25-1.39(2H,m), 1.48- 1.69(3H, m), 1.73-1.83 (2H, m), 1.93-2.01(2H, m), 2.31(3H, s),2.86(3H, s), 2.96(3H, s), 3.25-3.55(8H, m), 3.90-4.00(1H, m), 6.96(2H,d, J = 8.6 Hz), 7.34(1H, d, J = 8.6 Hz), 7.50(1H, brs) 438 108

colorless solid  98-103 CDCl₃ 1.21-1.36(1H, m), 1.38-1.52(2H, m), 1.72-1.98(5H, m), 2.15-2.24 (2H, m), 2.36(3H, s), 4.13- 4.23(1H, m), 7.53(1H,s), 7.64(2H, d, J = 8.6 Hz), 7.75(2H, d, J = 8.6 Hz), 7.89(1H, brs) 365

TABLE 56 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 109

colorless solid 250(decpt.) D₂O 1.12-1.26(1H, m), 1.31-1.44(2H, m),1.54- 1.64(3H, m), 1.80-1.88 (2H, m), 1.96-2.05(2H, m), 2.32(3H, s),3.00(3H, s), 3.17-3.30(2H, m), 3.34- 3.45(2H, m), 3.63-3.74(2H, m),3.95-4.05(1H, m), 4.18- 4.29(2H, m), 7.03(1H, d, J = 9.4 Hz), 7.55(1H,s), 7.82(1H, dd, J = 2.4 and 9.4 Hz), 8.25(1H, d, J = 2.4 Hz) 439 110

colorless cryst. 164-170 DMSO-d₆, 1.28-1.32(1H, m), 1.38-1.52(2H, m),1.64- 1.89(5H, m), 2.05-2.12(2H, m), 2.41 (3H, s), 2.63- 2.74(2H, m),2.76(3H, s), 3.09-3.12(2H, m), 3.41- 3.50(2H, m), 373-3.82(2H, m),4.20-4.30(1H, m), 7.47- 7.51(1H, m), 7.65-7.71(1H, m), 8.08-8.13(1H, m),8.17(1H, s), 8.26-8.28(1H, m), 10.22(1H, brs), 10.68(1H, brs) 502 111

coloeless solid 255-256 DMSO-d₆ 1.28-1.31(1H, m), 1.38-1.52(2H, m),1.64- 1.89(5H, m), 2.04-2.12(2H, m), 2.41(3H, s), 2.45(3H, s),4.17-4.27(1H, m), 7.44(1H, brs), 7.47-7.51(1H, m), 7.55-7.61(1H, m),7.89-8.04 (1H, m), 8.11(1H, s), 8.22- 8.26(1H, m), 10.51(1H, brs) 433112

pale yellow solid 203-205 CDCl₃ 1.52-1.75(6H, m), 1.78-1.88(2H, m),1.99- 2.11(2H, m), 2.15-2.24(2H, m), 2.35(3H, s), 2.45(3H, s),2.55-2.61(4H, m), 3.16-3.22 (4H, m), 4.34-4.43(1H, m), 6.92(2H, d. J =9.0 Hz), 7.43(1H, s), 7.46(2H, d, J = 9.0 Hz), 7.49(1H, brs) 452

TABLE 57 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 113

colorless foamy solid CDCl₃ 1.22-1.36(1H, m), 1.39-1.52(2H, m), 1.69-1.98(5H, m), 2.15-2.24(2H, m), 2.35(3H, s), 2.46(3H, s), 2.53-2.59(4H,m), 3.21-3.27 (4H, m), 4.13-4.23(1H, m), 6.67-6.72(1H, m), 6.88-6.93(1H, m), 7.19-7.25(1H, m), 7.40-7.43(1H, m), 7.45 (1H, s), 7.45(1H, brs)438 114

yellow cryst. 165-167 (iPrOH) DMSO-d₆, 1.18-1.32(1H, m), 1.37-1.53(4H,m), 1.64- 1.88(7H, m), 2.03-2.10 (2H, m), 2.39(3H, s), 2.75- 2.84(2H,m), 3.45-3.52(2H, m), 3.56-3.65(1H, m), 4.16- 4.26(1H, m), 4.65(1H, d, J= 4.2 Hz), 6.91(2H, d, J = 9.0 Hz), 7.52(2H, d, J = 9.0 Hz), 7.99(1H,s), 10.02(1H, brs) 439 115

colorless cryst. 205-207 (EtOH) CDCl₃ 1.56-1.75(6H, m), 1.80-1.88(2H,m), 2.00- 2.10(2H, m), 2.15-2.25(5H, m), 2.46(3H, s), 3.93(3H, s),4.33-4.43(1H, m), 6.74(1H, dd, J = 2.2 and 8.7 Hz), 7.47(1H, s),7.85(1H, brs), 7.70(1H, brs), 7.78(1H, d, J = 2.2 Hz), 8.31 (1H, d, J =8.7 Hz) 441 116

colorless cryst. 201-202 (iPr₂O/EtOAc) CDCl₃ 1.21-1.35(1H, m),1.38-1.52(2H, m), 1.71- 1.98(5H, m), 2.15-2.23(2H, m), 2.48(3H, s),4.15- 4.25(1H, m), 7.64(1H, s), 7.64(1H, brs), 8.55(2H, s) 409

TABLE 58 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 117

colorless solid 93-96 CDCl₃ 1.16-1.31(4H, m), 1.38-1.47(2H, m), 1.65-1.89(4H, m), 2.47(3H, s), 3.92(3H, s), 4.16-4.26(1H, m), 6.94(2H, d, J =8.3 Hz), 7.38 (2H, d, J = 8.3 Hz), 9.90(1H, s) 393 118

colorless solid 118-120 CDCl₃ 1.22-1.34(1H, m), 1.37-1.52(2H, m), 1.72-1.98(5H, m), 2.15-2.24 (2H, m), 2.45(3H, s), 4.14- 4.24(1H, m), 7.13(1H,s), 7.38-7.44(2H, m), 7.47- 7.52(2H, m) 375 119

pale yellow solid 182-183 CDCl₃ 1.22-1.48(3H, m), 1.70-1.95(5H, m),2.15- 2.24(2H, m), 2.36(3H, s), 2.44(3H, s), 2.56-2.61(4H, m),3.23-3.28(4H, m), 4.12-4.22 (1H, m), 6.88-6.94(2H, m), 6.98(1H, s),7.42-7.48(2H, m) 395 120

colorless cryst. 210-214 (EtOH/Et₂O) DMSO-d₆ 1.16-1.28(1H, m),1.38-1.50(2H, m), 1.65- 1.87(5H, m), 2.04-2.13(2H, m), 2.30(3H, s),2.34(3H, s), 2.85-2.88(3H, m), 2.93-3.21 (4H, m), 3.40-3.58(2H, m),3.82-3.97(2H, m), 4.12-4.22 (1H, m), 7.01-7.06(2H, m), 7.31(1H, s),7.48-7.53 (2H, m), 9.55(1H, brs) 395

TABLE 59 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 121

pale yellow solid 112-114 CDCl₃ 1.22-1.53(3H, m), 1.70-1.96(5H, m),1.99- 2.07(2H, m), 2.15-2.24(2H, m), 2.39(3H, s), 2.43(3H, s),2.56-2.61(2H, m), 2.71-2.76 (2H, m), 3.47-3.53(2H, m), 3.57-3.62(2H, m),4.12-4.22 (1H, m), 6.66-6.71(2H, m), 6.91(1H, s), 7.38-7.43(2H, m) 409122

colorless cryst. 127-129 CDCl₃ 1.22-1.33(1H, m), 1.37-1.50(2H, m), 1.70-1.96(5H, m), 2.13-2.21(2H, m), 2.41-2.46(1H, brs), 2.44(3H, s),3.59-3.65(2H, m), 3.81-3.87(2H, m), 4.18(1H, tt, J = 3.8 and 11.8 Hz),6.36-6.44(1H, m), 7.36(1H, s) 308 123

colorless viscous solid CDCl₃ 1.20-1.33(1H, m), 1.37-1.50(2H, m), 1.71-1.97(7H, m), 2.14-2.22 (2H, m), 2.43(3H, s), 2.85- 2.91(1H, m),3.59-3.65 (2H, m), 3.72-3.79(2H, m), 4.18(1H, tt, J = 3.8 and 11.8 Hz),6.42-6.48(1H, m), 7.34(1H, s) 322 124

pale yellow foamy solid CDCl₃ 1.22-1.35(1H, m), 1.39-1.53(2H, m), 1.71-1.97(5H, m), 2.15-2.25(3H, m), 2.46(3H, s), 2.84(3H, s), 3.20-3.26(2H,m), 3.72-3.79 (2H, m), 4.20(1H, tt, J = 3.8 and 11.8 Hz), 6.97-7.04(1H,m), 7.18(1H, dd, J = 1.9 and 8.6 Hz), 7.47(1H, s), 7.50(1H, dd, J = 2.3and 13.8 Hz), 7.58(1H, brs) 431

TABLE 60 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 125

colorless solid 112-125 DMSO-d₆ 1.18-1.30(1H, m), 1.37-1.50(2H, m),1.63- 1.88(5H, m), 2.02-2.10(2H, m), 2.40(3H, s), 2.89(3H, s),3.20-3.26(2H, m), 3.52-3.58 (2H, m), 4.22(1H, tt, J = 3.8 and 11.7 Hz),7.18-7.26 (1H, m), 7.39-7.45(1H, m), 7.64(1H, dd, J = 2.0 and 15.3 Hz),8.06(1H, s), 10.30(1H, brs) 431 126

colorless foamy solid CDCl₃ 1.22-1.34(1H, m), 1.28(3H, t, J = 7.1 Hz),1.37- 1.50(2H, m), 1.62-2.00 (13H, m), 2.14-2.22(2H, m), 2.44(3H, s),2.49-2.57 (1H, m), 4.08-4.22(2H, m), 4.16(2H, q, J = 7.1 Hz),5.84-5.90(1H, m), 7.32(1H, s) 418 127

colorless solid 212-213 CDCl₃ 1.20-2.06(16H, m), 2.13-2.22(2H, m),2.44(3H, s), 2.60-2.68(1H, m), 4.06- 4.23(2H, m), 5.82-5.89(1H, m),7.32(1H, s) 390 128

colorless solid 150-153 CDCl₃ 1.22-1.97(17H, m), 2.13-2.21 (2H, m),2.45(3H, s), 3.57-3.61(2H, m), 4.09- 4.27(2H, m), 5.93-5.98(1H, m),7.32(1H, s) 376

TABLE 61 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 129

colorless solid 147-148 CDCl₃ 0.98-1.11(2H, m), 1.21-1.35(1H, m), 1.38-1.50(4H, m), 1.53-1.65(1H, m), 1.72-1.97(7H, m), 2.00- 2.08(2H, m),2.14-2.21(2H, m), 2.26(1H, tt, J = 3.6 and 12.2 Hz), 2.44(3H, s), 3.28-3.34(2H, m), 3.67(3H, s), 4.18(1H, tt, J = 3.8 and 11.8 Hz),5.92-6.00(1H, m), 7.33(1H, s) 418 130

colorless cryst. 101-104 (EtOAc) CDCl₃ 0.92-1.10(4H, m), 1.21-1.34(2H,m), 1.36- 1.55(3H, m), 1.70-1.97(9H, m), 2.13-2.21(2H, m), 2.44(3H, s),3.28-3.34(2H, m), 3.46-3.51(2H, m), 4.18(1H, tt, J = 3.8 and 11.9 Hz),5.92-6.00(1H, m), 7.33(1H, s) 390 131

colorless solid 265(dec.) CDCl₃ 1.21-2.22(18H, m), 1.45(9H, s), 2.43(3H,s), 3.37-3.53(1H, m), 3.87-3.97 (1H, m), 4.17(1H, tt, J = 3.8 and 11.9Hz), 4.37-4.45 (1H, m), 5.66-5.72(1H, m), 7.31(1H, s) 461 132

colorless cryst. 154-156 (Et₂O) CDCl₃ 1.20-1.98(14H, m), 2.05-2.23(4H,s), 2.44(3H, s), 2.65-2.74(1H, m), 3.86- 3.96(1H, m), 4.18(1H, tt, J =3.8 and 11.8 Hz), 5.64- 5.69(1H, m), 7.30(1H, s) 361

TABLE 62 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 133

colorless solid 211-214 CDCl₃ 1.19-1.49(7H, m), 1.71-2.03(7H, m), 2.13-2.29(5H, m), 2.44(3H, s), 2.56-2.61(4H, m), 3.72- 3.77(4H, m),3.85-3.94(1H, m), 4.17(1H, tt, J = 3.9 and 11.8 Hz), 5.60-5.71 (1H, m),7.30(1H, s) 431 134

colorless solid 184-187 CDCl₃ 1.21-1.52(5H, m), 1.71-1.97(5H, m), 2.01-2.08 (2H, m), 2.04-2.11(2H, m), 2.44(3H, s). 2.70- 2.80(2H, m),3.08-3.15(2H, m), 3.99-4.10(1H, m), 4.18(1H, tt, J = 3.9 and 11.8 Hz),5.72-5.79(1H, m), 7.32(1H, s) 347 135

colorless solid 207-208 CDCl₃ 1.22-1.34(1H, m), 1.38-1.68(6H, m), 1.71-1.96(7H, m). 2.03-2.11 (2H, m), 2.13-2.21(2H, m), 2.30-2.39(2H, m),2.44(3H, s), 2.46-2.55(1H, m), 2.92- 3.00(2H, m), 3.35-3.45(2H, m),3.92-4.07(3H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 5.71-5.77(1H, m),7.31(1H, s) 431 136

colorless solid 217-220 CDCl₃ 1.22-1.96(18H, m), 2.01-2.09(2H, m), 2.13-2.21(2H, m), 2.36-2.49(3H, m), 2.44(3H, s), 2.87- 2.94(2H, m),3.77-3.84(1H, m), 3.81-4.01 (8H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz),5.76-5.80(1H, m), 7.31(1H, s) 487

TABLE 63 properties Example m.p. (° C.) MS(FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 137

colorless solid 207-210 CDCl₃ 1.21-2.22(18H, m), 2.28-2.54(4H, m),2.44(3H, s), 2.58-2.66(1H, m), 2.72- 2.82(1H, m), 2.93-3.01(2H, m),3.93-4.02(1H, m), 4.18 (1H, tt, J = 3.8 and 11.8 Hz), 5.73-5.79(1H, m),7.32(1H, s) 443 138

colorless solid 150-160 CDCl₃ 1.20-1.65(8H m), 1.69-1.98(8H, m), 2.00-2.10(4H, m), 2.13-2.20 (2H, m), 2.30-2.41 (3H, m), 2.44(3H, s),2.95-3.96(2H, m), 3.55-3.64(1H, m), 3.88- 4.01(1H, m), 4.17(1H, tt, J =3.8 and 11.8 Hz), 5.70- 5.77(1H, m), 7.31(1H, s) 445 139

colorless solid 197(dec.) CDCl₃ 1.22-1.33(1H, m), 1.37-1.64(4H, m),1.48(9H, s), 1.70-1.96(7H, m), 2.15- 2.21(2H, m), 2.45(3H, s),2.57-2.67(1H, m), 2.72-2.84 (2H, m), 4.12-4.30(3H, m), 7.18(2H, d, J =8.5 Hz), 7.46 (1H, s), 7.51(2H, d, J = 8.5 Hz), 7.63(1H, brs) 523 140

pale yellow foamy solid CDCl₃ 1.22-1.33(1H, m), 1.37-1.50(2H, m), 1.52-1.67(1H, m), 1.70-1.95(8H, m) 2.13-2.21(2H, m), 2.44(3H, s),2.55-2.64(1H, m), 2.68-2.78(2H, m), 3.13- 3.21(2H, m), 4.18(1H, tt, J =3.8 and 11.8 Hz), 7.20(2H, d, J = 8.4 Hz), 7.45(1H, s), 7.50(2H, d, J =8.4 Hz), 7.60(1H, brs) 423

TABLE 64 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 141

colorless cryst. 270 (dec.) (EtOH/Et₂O) DMSO-d₆ 1.14-1.28 (1H, m),1.35-1.48 (2H, m), 1.59- 1.93 (9H, m), 1.99-2.07 (2H, m), 2.47 (3H, s),2.74- 2.84 (1H, m), 2.90-3.01 (2H, m), 3.26-3.36 (2H, m), 4.18 (1H, tt,J = 3.8 and 11.8 Hz), 7.18 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5Hz), 8.06 (1H, s), 8.42-8.58 (1H, m), 8.63-8.77 (1H, m), 10.21 (1H, brs)423 142

colorless foamy solid CDCl₃ 1.20-1.33 (1H, m), 1.37-1.51 (2H, m), 1.69-1.95 (9H, m), 1.98-2.07 (2H, m), 2.12-2.21 (2H, m), 2.31 (3H, s),2.39-2.49 (1H, m), 2.45 (3H, s), 2.92- 3.00 (2H, m), 4.18 (1H, tt, J =3.8 and 11.8 Hz), 7.21 (2H, d, J = 8.5 Hz), 7.44 (1H, s), 7.50 (2H, d, J= 8.5 Hz), 7.57 (1H, brs) 437 143

pale brown solid 197-198 CDCl₃ 1.12 (3H, t, J = 7.3 Hz), 1.21-1.33 (1H,m), 1.37- 1.51 (2H, m), 1.69-1.96 (5H, m), 2.15-2.22 (2H, m), 2.45 (3H,s), 2.48 (2H, q, J = 7.3 Hz), 2.58-2.66 (4H, m), 3.07-3.14 (4H, m), 4.18(1H, tt, J = 3.8 and 11.8 Hz), 6.89-6.97 (1H, m), 7.15 (1H, dd, J = 1.6and 8.6 Hz), 7.43 (1H, s), 7.46-7.53 (1H, m), 7.51 (1H, brs) 470 144

brown foamy solid CDCl₃ 1.21-1.33 (1H, m), 1.37-1.50 (2H, m), 1.69- 2.04(7H, m), 2.12-2.21 (2H, m), 2.39 (3H, s), 2.44 (3H, s), 2.62-2.67 (2H,m), 2.73- 2.78 (2H, m), 3.35-3.44 (4H, m), 4.17 (1H, tt, J = 3.8 and11.8 Hz), 6.76-6.83 (1H, m), 7.09 (1H, dd, J = 1.9 and 8.9 Hz), 7.43(1H, s), 7.48 (1H, dd, J = 2.4 and 11.6 Hz), 7.42 (1H, s), 7.51 (1H,brs) 470

TABLE 65 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 145

colorless solid 216-218 (AcOEt/hexane) CDCl₃ 1.21-1.52 (3H, m), 1.38(3H, t, J = 7.1 Hz), 1.71- 1.99 (5H, m), 2.16-2.25 (2H, m), 2.45 (3H,s), 3.92 (3H, s), 4.13-4.22 (1H, m), 4.35 (2H, q, J = 7.1 Hz), 6.95 (1H,dd, J = 1.8 and 8.4 Hz), 7.52 (1H, s), 7.72 (1H, d, 1.8 Hz), 7.84 (1H,d, J = 8.4 Hz), 7.92 (1H, brs) 442 146

colorless solid 223-224.5 (AcOEt) DMSO-d₆ 1.15-1.30 (1H, m), 1.38-1.51(2H, m), 1.62- 1.90 (5H, m), 2.02-2.13 (2H, m), 2.41 (3H, s), 3.83 (3H,s), 4.17-4.29 (1H, m), 7.43 (1H, dd, J = 1.6 and 8.5 Hz), 7.59 (1H, d,1.6 Hz), 7.72 (1H, d, J = 8.5 Hz), 8.12 (1H, s), 10.41 (1H, brs), 12.31(1H, brs) 414 147

colorless solid 193.5-198 DMSO-d₆ 1.17-1.31 (1H, m), 1.39-1.51 (2H, m),1.62- 1.90 (5H, m), 2.02-2.13 (2H, m), 2.41 (3H, s), 2.78 (3H, s),2.88-3.08 (2H, m), 3.19-3.60 (5H, m), 3.84 (3H, s), 4.17- 4.29 (1H, m),4.51-4.64 (1H, m), 7.19-7.29 (1H, m), 7.41- 7.54 (1H, m), 7.59-7.68 (1H,m), 8.21 (1H, s), 10.50 (1H, brs), 11.20 (1H, brs) 496 148

colorless solid 188.5-190 (AcOEt/hexane) CDCl₃ 1.21-1.35 (1H, m), 1.39-1.1.52 (2H, m), 1.71- 2.00 (5H, m), 2.13-2.25 (2H, m), 2.50 (3H, s),3.19- 3.39 (2H, m), 3.51-3.65 (2H, m), 3.70-3.97 (4H, m), 3.77 (3H, s),4.14-4.26 (1H, m), 6.80 (1H, dd, J = 1.8 and 8.1 Hz), 7.04 (1H, d, J =8.1 Hz), 7.37 (1H, d, J = 1.7 Hz), 7.76 (1H, s), 8.72 (1H, brs) 483

TABLE 66 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 149

colorless solid 242.5-245.5 CDCl₃ 1.21-1.69 (6H, m), 1.71-2.00 (7H, m),2.13- 2.25 (2H, m), 4.46 (3H, s), 2.99-3.18 (1H, m), 3.34- 3.59 (2H, m),3.70-3.80 (3H, m), 3.90-4.00 (1H, m), 4.13- 4.34 (2H, m), 6.77-6.82 (1H,m), 6.95-7.03 (1H, m), 7.29- 7.36 (1H, m), 7.82 (1H, s), 8.84 (1H, brs)497 150

colorless solid 243-245.5 CDCl₃ 1.21-1.36 (1H, m), 1.39- 1.51 (2H, m),1.70- 2.00 (5H, m), 2.15-2.25 (2H, m), 3.27 (1H, brt, J = 5.2 Hz),3.60-3.69 (2H, m), 3.79-3.89 (2H, m), 3.99 (3H, s), 4.13- 4.25 (1H, m),6.88 (1H, dd, J = 1.8 and 8.5 Hz), 7.58 (1H, s), 7.93 (1H, d, J = 1.8Hz), 8.13 (1H, d, J = 8.5 Hz), 8.15 (1H, brs), 8.26 (1H, brt, 5.5 Hz)457 151

colorless solid 187-188 CDCl₃ 1.21-1.35 (1H, m), 1.39-1.52 (2H, m),1.71- 1.99 (5H, m), 2.14-2.24 (2H, m), 2.44 (3H, s), 3.41 (3H, s),3.52-3.60 (2H, m), 3.62-3.70 (2H, m), 3.99 (3H, s), 4.13- 4.24 (1H, m),6.89 (1H, dd, J = 1.5 and 8.5 Hz), 7.57 (1H, s), 7.95 (1H, d, J = 1.5Hz), 8.11 (1H, brs), 8.16 (1H, d, J = 8.5 Hz), 8.19 (1H, brt, 5.3 Hz)471 152

colorless solid 279-281 (AcOEt) CDCl₃ 1.22-1.36 (1H, m), 1.39-1.52 (2H,m), 1.71- 1.99 (5H, m), 2.14-2.23 (2H, m), 2.45 (3H, s), 3.01 (3H, d, J= 4.8 Hz), 4.00 (3H, s), 4.13- 4.23 (1H, m), 6.87 (1H, dd, J = 1.8 and8.5 Hz), 7.56 (1H, s), 7.81 (1H, brq, J = 4.8 Hz), 7.97 (1H, d, J = 1.8Hz), 8.04 (1H, brs), 8.19 (1H, d, J = 8.5 Hz) 427

TABLE 67 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 153

colorless solid 216-218 (AcOEt) CDCl₃ 1.21-1.37 (1H, m), 1.39-1.52 (2H,m), 1 .70- 1.98 (5H, m), 2.15-2.25 (2H, m), 2.47 (3H, s), 2.87 (3H, s),3.16 (3H, s), 3.73 (3H, s), 4.13-4.24 (1H, m), 6.79 (1H, dd, J = 1.4 and8.1 Hz), 6.98 (1H, d, J = 8.1 Hz), 7.28 (1H, d, J = 1.4 Hz), 7.88 (1H,s), 8.98 (1H, brs) 441 154

colorless solid 169-172.5 (EtOH) CDCl₃ 1.21-1.34 (1H, m), 1.38-1.51 (2H,m), 1.69- 1.97 (5H, m), 2.12-2.21 (2H, m), 2.34 (3H, s), 2.44 (3H, s),2.53-2.64 (4H, m), 3.03-3.14 (4H, m), 4.11-4.21 (1H, m), 6.89-6.96 (1H,m), 7.15 (1H, dd J = 2.4 and 8.6 Hz), 7.43 (1H, s), 7.49 (1H, dd J = 2.4and 14.0 Hz), 7.53 (1H, brs) 456 155

colorless solid 270 (dec.) DMSO-d₆ 1.15-1.29 (1H, m), 1.34-1.49 (2H, m),1.60- 1.88 (5H, m) 1.99-2.09 (2H, m), 2.30 (3H, s), 2.37 (3H, s), 2.84(3H, s), 2.90-3.62 (8H, m), 4.13-4.27 (1H, m), 7.08- 7.14 (1H, m),7.39-7.45 (1H, m), 7.62-7.71 (1H, m), 8.02 (1H, s), 9.56 (1H, brs),10.28 (1H, brs) 456 156

colorless solid 114-118 (EtOH) CDCl₃ 1.21-1.35 (1H, m), 1.40- 1.52 (2H,m), 1.71- 1.98 (5H, m), 2.14-2.23 (2H, m), 2.39 (3H, s), 2.46 (3H, s),2.54-2.72 (4H, m), 3.00-3.17 (4H, m), 4.14-4.26 (1H, m), 7.05 (1H, d, J= 8.7 Hz), 7.43 (1H, dd, J = 2.4 and 8.7 Hz), 7.46 (1H, s), 7.57 (1H,brs), 7.69 (1H, d, J = 2.4 Hz) 472

TABLE 68 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 157

colorless solid 188-189.5 (EtOH) CDCl₃ 1.21-1.35 (1H, m), 1.39-1.51 (2H,m), 1.70- 1.98 (9H, m), 2.14-2.23 (2H, m), 2.45 (3H, s), 3.11- 3.19 (4H,m), 4.00 (4H, s), 4.12-4.24 (1H, m), 6.91- 6.98 (1H, m), 7.16 (1H, dd J= 2.4 and 8.6 Hz), 7.46 (1H, s), 7.49 (1H, dd, J = 2.4 and 13.9 Hz),7.61 (1H, brs) 499 158

colorless solid 198-199 (EtOH) CDCl₃ 1.21-1.35 (1H, m), 1.39-1.52 (2H,m), 1.70- 1.99 (5H, m), 2.16-2.25 (2H, m), 2.46 (3H, s), 2.59- 2.68 (4H,m), 3.34-3.43 (4H, m), 4.14-4.25 (1H, m), 6.94- 7.01 (1H, m), 7.18-7.23(1H, m), 7.47 (1H, s), 7.56 (1H, dd, J = 2.4 and 13.7 Hz), 7.62 (1H,brs) 455 159

colorless solid 210-212 (EtOH) CDCl₃ 1.21-1.34 (1H, m), 1.39-1.52 (3H,m), 1.70- 1.98 (7H, m), 2.00-2.09 (2H, m), 2.16-2.24 (2H, m), 2.46 (3H,s), 279-2.89 (2H, m), 3.29-3.39 (2H, m), 3.81- 3.91 (1H, m), 4.13-4.24(1H, m), 6.91-7.00 (1H, m), 7.17 (1H, dd, J = 2.5 and 8.6 Hz), 7.46 (1H,s), 7.48 (1H, dd, J = 2.5 and 13.9 Hz), 7.58 (1H, brs) 457 160

colorless solid 230.5-232 (EtOH) CDCl₃ 1.22-1.36 (1H, m), 1.39-1.52 (2H,m), 1.71- 1.98 (9H, m), 2.15-2.23 (2H, m), 2.45 (3H, s), 3.05- 3.16 (4H,m), 4.01 (4H, s), 4.15-4.24 (1H, m), 7.05 (1H, d, J = 8.7 Hz), 7.44 (1H,dd, J = 2.5 and 8.7 Hz), 7.46 (1H, s), 7.58 (1H, brs), 7.66 (1H, d, J =2.5 Hz) 515

TABLE 69 Ex- properties am- m.p. (° C.) ple (recryst. MS (FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 161

colorless solid 217.5-219 (EtOH) CDCl₃ 1.21-1.37 (1H, m), 1.40-1.52 (2H,m), 1.71- 1.99 (5H, m), 2.15-2.24 (2H, m), 2.46 (3H, s), 2.60- 2.70 (4H,m), 3.29-3.38 (4H, m), 4.13-4.26 (1H, m), 7.05 (1H, d, J = 8.7 Hz), 7.47(1H, dd, J = 2.5 and 8.7 Hz), 7.48 (1H, s), 7.64 (1H, brs), 7.73 (1H, d,J = 2.5 Hz) 471 162

colorless solid 153.5-156 (AcOEt/ hexane) CDCl₃ 1.21-1.36 (1H, m),1.39-1.53 (3H, m), 1.71- 1.99 (7H, m), 2.01-2.10 (2H, m), 2.16-2.24 (2H,m), 2.45 (3H, s), 275-2.87 (2H, m), 3.21-3.31 (2H, m), 3.82- 3.92 (1H,m), 4.14-4.26 (1H, m), 7.03 (1H, d, J = 8.7 Hz), 7.44 (1H, dd, J = 2.5and 8.7 Hz), 7.47 (1H, s), 7.63 (1H, brs), 7.65 (1H, d, J = 2.5 Hz) 473163

colorless solid 174-176 (AcOEt/ hexane) CDCl₃ 1.22-1.36 (1H, m),1.39-1.63 (4H, m), 1.71- 2.07 (7H, m), 2.14-2.23 (2H, m), 2.41-2.56 (1H,m), 2.46 (3H, s), 2.48 (3H, s), 2.68-2.80 (2H, m), 3.38- 3.45 (2H, m),4.14-4.23 (1H, m), 6.90-6.99 (1H, m), 7.17 (1H, dd, J = 2.4 and 8.6 Hz),7.42-7.51 (2H, m), 7.58 (1H, brs) 470 164

colorless solid 99.5-106.5 CDCl₃ 1.22-1.36 (1H, m), 1.39-1.52 (2H, m),1.49 (9H, s), 1.70-2.00 (9H, m), 2.14- 2.24 (2H, m), 2.46 (3H, s),2.67-2.77 (2H, m), 2.81 (3H, s), 3.37-3.46 (2H, m), 4.10-4.26 (2H, m),7.00-7.07 (1H, m), 7.39-7.45 (1H, m), 7.47 (1H, s), 7.59-7.62 (1H, m),7.69 (1H, brs) 586

TABLE 70 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 165

colorless solid 112-121 CDCl₃ 1.22-1.37 (1H, m), 1.39-1.65 (4H, m),1.71- 2.08 (7H, m), 2.16-2.25 (2H, m), 2.46 (3H, s), 2.49 (3H, s),2.50-2.58 (1H, m), 265-2.76 (2H, m), 3.30-3.39 (2H, m), 4.12-4.24 (1H,m), 7.04 (1H, d, J = 8.7 Hz), 7.45 (1H, dd, J = 2.4 and 8.7 Hz), 7.46(1H, s), 7.56 (1H, brs), 7.64 (1H, d, J = 2.4 Hz) 486 166

colorless solid 230-233.5 (AcOEt) CDCl₃ 1.17-1.32 (3H, m), 1.36-1.49(4H, m), 1.69- 2.00 (7H, m), 2.10-2.20 (4H, m), 2.22-2.30 (1H, m), 2.27(3H, s), 2.37-2.70 (8H, m), 2.41 (3H, s), 3.81- 3.92 (1H, m), 4.09-4.21(1H, m), 5.62-5.69 (1H, m), 7.28 (1H, s) 444 167

colorless solid 195-199 (AcOEt) CDCl₃ 1.17-1.32 (3H, m), 1.36-1.50 (4H,m), 1.69- 1.95 (9H, m), 2.09-2.20 (4H, m), 2.34 (3H, s), 2.41 (3H, s),2.42-2.50 (1H, m), 2.52-2.62 (4H, m), 2.71-2.80 (4H, m), 3.80-3.91 (1H,m), 4.10-4.20 (1H, m), 5.61-5.69 (1H, m), 7.28 (1H, s) 458 168

colorless solid 204.5-207 (AcOEt/hexane) CDCl₃ 1.18-1.32 (3H, m),1.36-1.49 (4H, m), 1.51- 1.61 (2H, m), 1.69-1.95 (9H, m), 2.10-2.20 (4H,m), 2.25- 2.38 (3H, m), 2.41 (3H, s), 2.72-2.81 (2H, m), 3.13- 3.22 (1H,m), 3.32 (3H, s), 3.80-3.93 (1H, m), 4.11- 4.21 (1H, m), 5.62-5.69 (1H,m), 7.28 (1H, s) 459

TABLE 71 Ex- properties am- m.p. (° C.) MS ple (recryst. (FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 169

colorless solid 61-63 CDCl₃ 1.12-1.50 (7H, m), 1.68-1.95 (9H, m), 2.05-2.20 (4H, m), 2.35-2.50 (1H, m), 2.41 (3H, s), 2.57- 2.78 (4H, m),3.41-3.59 (4H, m), 3.76-3.90 (1H, m), 4.08- 4.21 (1H, m), 5.13 (2H, s),5.60-5.71 (1H, m), 7.28- 7.40 (6H, m) 578 170

colorless solid 115-120 CDCl₃ 1.17-1.32 (3H, m), 1.36-1.50 (4H, m),1.64- 1.96 (9H, m), 2.09-2.21 (4H, m), 2.41 (3H, s), 2.43- 2.54 (1H, m),2.68-2.77 (4H, m), 2.83-2.94 (4H, m), 3.80- 3.92 (1H, m), 4.10-4.21 (1H,m), 5.61-5.70 (1H, m), 7.28 (1H, s) 444 171

colorless foamy solid CDCl₃ 1.17-1.50 (7H, m), 1.69-1.97 (9H, m), 2.07and 2.08 (total 3H, each s), 2.10- 2.21 (4H, m), 2.41 (3H, s), 2.44-2.54(1H, m), 2.61-2.69 (2H, m), 2.71-2.79 (2H, m), 3.41-3.52 (2H, m),3.55-3.12 (2H, m), 3.79-3.92 (1H, m), 4.11-4.21 (1H, m), 5.64-5.72 (1H,m), 7.28 (1H, s) 486 172

colorless solid 142-143.5 (AcOEt/ hexane) CDCl₃ 1.17-1.32 (3H, m),1.35-1.49 (4H, m), 1.69- 1.96 (7H, m), 2.10-2.20 (4H, m), 2.30 (3H, s),2.39- 2.48 (1H, m), 2.41 (3H, s), 2.63 (2H, t, J = 5.9 Hz), 3.35 (3H,s), 3.45 (2H, t, J = 5.9 Hz), 3.80-3.92 (1H, m), 4.10-4.20 (1H, m),5.61-5.69 (1H, m), 7.28 (1H, s) 433

TABLE 72 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 173

colorless foamy solid CDCl₃ 1.20-1.97 (16H, m), 2.11-2.20 (2H, m), 2.28-2.47 (1H, m), 2.33 (3H, s), 2.44 (3H, s), 2.68 (2H, t, J = 6.0 Hz), 3.35(3H, s), 3.47 (2H, t, J = 6.0 Hz), 4.11- 4.24 (2H, m), 5.93-6.00 (1H,m), 7.30 (1H, s) 433 174

colorless solid 222-224.5 (EtOH) CDCl₃ 1.16-1.31 (3H, m), 1.35-1.50 (4H,m), 1.68- 1.96 (11H, m), 2.09-2.19 (4H, m), 2.31-2.40 (1H, m), 2.41 (3H,s), 2.58-2.67 (4H, m), 3.80-3.92 (1H, m), 3.94 (4H, s), 4.10-4.20 (1H,m), 5.62-5.71 (1H, m), 7.28 (1H, s) 487 175

colorless solid 197-199 (AcOEt) CDCl₃ 1.19-1.32 (3H, m), 1.36- 1.52 (4H,m), 1.69- 2.00 (7H, m), 2.10-2.23 (4H, m), 2.36-2.56 (8H, m), 2.79- 2.89(4H, m), 3.82-3.95 (1H, m), 4.10-4.20 (1H, m), 5.66- 5.76 (1H, m), 7.29(1H, s) 443 176

colorless solid 200-202 (AcOEt) CDCl₃ 1.18-1.31 (3H, m), 1.36- 1.97(16H, m), 2.10- 2.20 (4H, m), 2.27-2.38 (3H, m), 2.41 (3H, s), 2.75-2.85 (2H, m), 3.61-3.71 (1H, m), 3.80-3.92 (1H, m), 4.10- 4.20 (1H, m),5.64-5.73 (1H, m), 7.28 (1H, s) 445

TABLE 73 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 177

colorless solid 226-228 (EtOH) CDCl₃ 1.15 (6H, d, J = 6.2 Hz), 1.17-1.32(3H, m), 1.34- 1.50 (4H, m), 1.69-1.99 (9H, m), 2.11-2.27 (5H, m), 2.41(3H, s), 2.68-2.78 (2H, m), 3.59-3.69 (2H, m), 3.81- 3.93 (1H, m),4.11-4.20 (1H, m), 5.63-5.70 (1H, m), 7.28 (1H, s) 459 178

colorless solid 199.5-200.5 (EtOH) CDCl₃ 1.17 (6H, d, J = 6.2 Hz),1.20-1.33 (1H, m), 1.36- 1.50 (2H, m), 1.53-1.96 (15H, m), 2.09-2.20(3H, m), 2.43 (3H, s), 2.80-2.89 (2H, m), 3.60-3.70 (2H, m), 4.10- 4.22(2H, m), 5.89-5.96 (1H, m), 7.30 (1H, s) 459 179

colorless solid 201.5-203 (AcOEt/hexane) CDCl₃ 1.17-1.98 (18H, m),2.10-2.38 (8H, m), 2.41 (6H, s), 2.81-2.90 (2H, m), 3.80- 3.92 (1H, m),4.11-4.20 (1H, m), 5.62-5.69 (1H, m), 7.29 (1H, s) 458 180

colorless solid 253-255 (AcOEt/EtOH) CDCl₃ 1.18-1.31 (3H, m), 1.35-1.50(4H, m), 1.57- 2.00 (11H, m), 2.07 and 2.10 (total 3H, each s), 2.11-2.21 (4H, m), 2.24-2.40 (3H, m), 2.41 (3H, s), 2.81 and 2.85 (total 3H,each s), 2.90- 3.01 (2H, m), 3.41- 3.51 (0.4H, m), 3.81-3.94 (1H, m),4.10-4.21 (1H, m), 4.41-4.52 (0.6H, m), 5.67- 5.74 (1H, m), 7.29 (1H, s)500

TABLE 74 Ex- properties am- m.p. (° C.) ple (recryst. MS (FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 181

colorless solid 204-208.5 (AcOEt) CDCl₃ 1.18-1.33 (3H, m), 1.36-1.50(4H, m), 1.55- 1.99 (11H, m), 2.10-2.20 (4H, m), 2.23-2.48 (4H, m), 2.38(6H, s), 2.41 (3H, s), 2.95-3.05 (2H, m), 3.80- 3.92 (1H, m), 4.10-4.20(1H, m), 5.68-5.74 (1H, m), 7.29 (1H, s) 472 182

colorless solid 215.5-224 CDCl₃ 1.16-1.50 (9H, m), 1.43 (9H, s),1.69-1.99 (9H, m), 2.10-2.19 (4H, m), 2.22- 2.36 (3H, m), 2.41 (3H, s),2.78-2.87 (2H, m), 3.36-3.49 (1H, m), 3.81-3.92 (1H, m), 4.09-4.20 (1H,m), 4.35-4.44 (1H, m), 5.62-5.69 (1H, m), 7.28 (1H, s) 544 183

colorless solid CDCl₃ 1.20-2.00 (20H, m), 1.44 (9H, s), 2.11-2.28 (5H,m), 2.43 (3H, s), 2.40-2.49 (2H, m), 3.38-3.51 (1H, m), 4.11-4.22 (2H,m), 4.33-4.46 (1H, m), 5.90-5.97 (1H, m), 7.30 (1H, s) 544 184

colorless solid 219-221.5 (AcOEt/ hexane) CDCl₃ 1.16-1.52 (9H, m),1.69-1.96 (9H, m), 2.10- 2.38 (7H, m), 2.41 (3H, s), 2.57-2.68 (1H, m),2.80- 2.89 (2H, m), 3.80-3.92 (1H, m), 4.10-4.21 (1H, m), 5.62- 5.70(1H, m), 7.28 (1H, s) 444

TABLE 75 Ex- am- properties ple m.p. (° C.) MS (FAB) No. ChemicalStructure (recryst. solvent) ¹H-NMR (M + 1)⁺ 185

colorless solid 83-86.5 CDCl₃ 1.20-1.95 (20H, m), 2.02-2.36 (5H, s),2.43 (3H, s), 2.60-2.70 (1H, m), 2.92- 3.03 (2H, m), 4.11-4.22 (2H, m),5.91-6.00 (1H, m), 7.30 (1H, s) 444 186

colorless solid 190.5-193.5 CDCl₃ 1.17-1.32 (3H, m), 1.36-1.49 (4H, m),1.45 (9H, s), 1.69-1.96 (7H, m), 2.11- 2.21 (4H, m), 2.25-2.36 (1H, m),2.41 (3H, s), 2.45-2.53 (4H, m), 3.38-3.45 (4H, m), 3.81-3.93 (1H, m),4.10-4.20 (1H, m), 5.63-5.70 (1H, m), 7.28 (1H, s) 530 187

colorless foamy solid CDCl₃ 1.20-1.96 (16H, m), 1.45 (9H, s), 2.11-2.24(3H, m), 2.43 (3H, s), 2.45-2.51 (4H, m), 3.39-3.47 (4H, m), 4.10-4.21(2H, m), 5.88-5.93 (1H, m), 7.30 (1H, s) 530 188

colorless solid 180.5-182 (AcOEt) CDCl₃ 1.18-1.32 (3H, m), 1.34-1.49(4H, m), 1.69- 1.99 (7H, m), 2.10-2.19 (4H, m), 2.20-2.29 (1H, m), 2.41(3H, s), 2.48-2.58 (4H, m), 2.82-2.91 (4H, m), 3.80- 3.93 (1H, m),4.10-4.20 (1H, m), 5.63-5.70 (1H, m), 7.28 (1H, s) 430

TABLE 76 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 189

colorless solid 161-164.5 CDCl₃ 1.20-1.96 (16H, m), 2.11-2.21 (3H, m),2.43 (3H, s), 2.46-2.58 (4H, m), 2.87- 2.96 (4H, m), 4.10-4.22 (2H, m),5.90-5.99 (1H, m), 7.30 (1H, s) 430 190

colorless solid 242-243.5 (AcOEt/EtOH) CDCl₃ 1.18-1.32 (3H, m),1.35-1.50 (4H, m), 1.69- 1.96 (7H, m), 2.07 (3H, s), 2.11-2.21 (4H, m),2.27- 2.38 (1H, m), 2.41 (3H, s), 2.49-2.59 (4H, m), 3.40- 3.47 (2H, m),3.57-3.63 (2H, m), 3.81-3.93 (1H, m), 4.10- 4.21 (1H, m), 5.64-5.71 (1H,m), 7.28 (1H, s) 472 191

pale brown solid 237 (dec.) DMSO-d₆ 1.16-1.29 (1H, m), 1.35-1.50 (2H,m), 1.61- 1.84 (5H, m), 1.881.96 (2H, m), 2.00-2.08 (2H, m), 2.35 (3H,s), 2.36 (3H, s), 2.63-2.69 (2H, m), 2.72- 2.77 (2H, m), 3.25-3.35 (4H,m), 4.19 (1H, tt, J = 3.8 and 11.7 Hz), 6.51 (1H, s), 6.88- 6.95 (1H,m), 7.29 (1H, dd, J = 2.0 and 8.8 Hz), 7.55 (1H, dd, J = 2.3 and 15.7Hz), 7.98 (1H, s), 10.15 (1H, brs) 470 192

colorless solid CDCl₃ 1.64-1.73 (2H, m), 2.00-2.10 (2H, m), 2.10 (3H,s), 3.22 (2H, s), 3.43-3.52 (2H, m), 4.02-4.09 (2H, m), 4.23 (1H, tt, J= 11.7 and 4.2 Hz) 183

TABLE 77 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 193

colorless solid CDCl₃ 1.80-1.88 (2H, m), 2.22-2.35 (2H, m), 2.46 (3H,s), 3.50-3.58 (2H, m), 4.09- 4.15 (2H, m), 4.48 (1H, tt, J = 11.6 and4.2 Hz), 9.89 (1H, s) 229 194

colorless solid 78-80 CDCl₃ 1.38 (3H, t, J = 7.1 Hz), 2.08-2.25 (4H, m),2.45 (3H, s), 3.52-3.61 (2H, m), 4.10-4.17 (2H, m), 4.35 (2H, q, J = 7.1Hz), 4.38-4.47 (1H, m), 7.71 (1H, s) 295 195

colorless solid 240-242 DMSO-d₆ 1.90-2.05 (4H, m), 2.38 (3H, s), 3.44-3.52 (2H, m), 3.92-4.00 (2H, m), 4.43-4.54 (1H, m), 7.66 (1H, s) 267 196

colorless solid 107-109 (EtOH) CDCl₃ 2.08-2.26 (4H, m), 2.36 (3H, s),2.46 (3H, s), 2.55-2.61 (4H, m), 3.16- 3.23 (4H, m), 3.52-3.61 (2H, m),4.09-4.16 (2H, m), 4.37-4.47 (1H, m), 6.90-6.95 (2H, m), 7.45 (1H, s),7.45-7.50 (2H, m), 7.53 (1H, brs) 440

TABLE 78 properties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 197

colorless solid 98-102 (EtOH) CDCl₃ 2.07-2.25 (4H, m), 2.36 (3H, s),2.46 (3H, s), 2.57-2.63 (4H, m), 3.06-3.12 (4H, m), 3.50-3.58 (2H, m),4.08-4.15 (2H, m), 4.36-4.47 (1H, m), 6.89-6.96 (1H, m), 7.12-7.16 (1H,m), 7.45 (1H, s), 7.47-7.52 (1H, m), 7.52 (1H, brs) 458 198

colorless foamy solid CDCl₃ 1.23-1.36 (1H, m), 1.38-1.52 (2H, m), 1.72-1.98 (5H, m), 2.15-2.25 (2H, m), 2.41-2.47 (4H, m), 2.46 (3H, s), 3.48(2H, s), 3.69-3.75 (4H, m), 4.19 (1H, tt, J = 3.8 and 11.8 Hz), 7.32(2H, d, J = 8.4 Hz), 7.47 (1H, s), 7.54 (2H, d, J = 8.4 Hz), 7.65 (1H,brs) 439 199

colorless solid 198-202 (Et₂O/EtOH) DMSO-d₆ 1.16-1.31 (1H, m), 1.38-1.52(2H, m), 1.62- 1.86 (5H, m), 2.01-2.11 (2H, m), 2.31-2.39 (4H, m), 2.40(3H, s), 3.44 (2H, s), 3.54-3.60 (4H, m), 4.22 (1H, tt, J = 3.8 and 11.6Hz), 6.62 (2H, s), 7.27 (2H, d, J = 8.5 Hz), 7.67 (2H, d, J = 8.5 Hz),8.06 (1H, s), 10.21 (1H, s) 439 200

colorless solid 140-144 (Et₂O/hexane) CDCl₃ 1.21-1.33 (1H, m), 1.38-1.51(2H, m), 1.71- 1.96 (5H, m), 2.14-2.23 (2H, m), 2.31 (6H, m), 2.46 (3H,s), 2.50-2.56 (2H, m), 2.65-2.71 (2H, m), 4.19 (1H, tt, J = 3.9 and 11.8Hz), 7.18- 7.23 (2H, m), 7.46 (1H, s), 7.49-7.54 (2H, m), 7.58 (1H, brs)411

TABLE 79 Ex- properties am- m.p. (° C.) ple (recryst. MS(FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 201

colorless solid 162-164 CDCl₃ 1.24-1.36 (1H, m), 1.39-1.52 (2H, m),1.72- 1.98 (5H, m), 2.15-2.24 (2H, m), 2.46 (3H, s), 2.49-2.55 (4H, m),2.56- 2.62 (2H, m), 2.76-2.83 (2H, m), 3.73-3.78 (4H, m), 4.19 (1H, tt,J = 3.9 and 11.8 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.46 (1H, s), 7.51 (2H,d, J = 8.4 Hz), 7.61 (1H, brs) 453 202

colorless foamy solid 216-218 CDCl₃ 1.24-1.35 (1H, m), 1.39-1.52 (2H,m), 1.72- 1.99 (5H, m), 2.16-2.24 (2H, m), 2.46 (3H, s), 2.99 (3H, s),3.86 (2H, s), 4.19 (1H, tt, J = 3.9 and 11.8 Hz), 4.63 (2H, s), 7.41-7.46 (2H, m), 7.47 (1H, s), 7.53-7.57 (2H, m), 7.63 (1H, brs) 466 203

colorless solid (AcOEt) CDCl₃ 1.22-1.53 (3H, m), 1.72-1.99 (5H, m),2.16- 2.24 (2H, m), 2.47 (3H, s), 3.10 (3H, s), 4.04 (2H, s), 4.19 (1H,tt, J = 3.9 and 11.8 Hz), 7.36-7.42 (2H, m), 7.51 (1H, s), 7.66-7.72(2H, m), 7.79 (1H, brs) 452 204

colorless solid 153-156 CDCl₃ 1.18-1.33 (3H, m), 1.38-1.51 (2H, m),1.55- 1.67 (2H, m), 1.71-1.96 (5H, m), 2.03-2.22 (6H, m), 2.28 (1H, tt,J = 3.6 and 12.1 Hz), 2.43 (3H, s), 3.68 (3H, s), 3.88- 4.00 (1H, m),4.16 (1H, tt, J = 3.9 and 11.9 Hz), 5.69-5.75 (1H, m), 7.30 (1H, s) 404

TABLE 80 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 205

colorless solid 280-288 DMSO-d₆ 1.16-1.49 (7H, m), 1.62-2.08 (11H, m),2.17 (1H, tt, J = 3.4 and 11.5 Hz), 2.35 (3H, s), 3.60-3.72 (1H, m),4.18 (1H, tt, J = 3.8 and 11.5 Hz), 7.80 (1H, s), 8.26 (1H, d, J = 7.8Hz), 12.12 (1H, brs) 390 206

colorless solid 180-182 CDCl₃ 1.07-1.56 (8H, m), 1.70-1.95 (7H, m),2.11- 2.20 (4H, m), 2.43 (3H, s), 3.46-3.52 (2H, m), 3.85- 3.97 (1H, m),4.17 (1H, tt, J = 3.8 and 11.9 Hz), 5.66- 5.72 (1H, m), 7.30 (1H, s) 376207

colorless foamy solid CDCl₃ 1.19-1.35 (3H, m), 1.37-1.51 (2H, m), 1.69-1.96 (9H, m), 2.13-2.25 (4H, m), 2.32 (3H, s), 2.34-2.49 (5H, m), 2.43(3H, s), 3.47-3.55 (2H, m), 3.60-3.67 (2H, m), 3.88- 4.01 (1H, m), 4.17(1H, tt, J = 3.9 and 11.9 Hz), 5.65- 5.71 (1H, m), 7.31 (1H, s) 472 208

colorless solid 224-228 CDCl₃ 1.21-1.52 (5H, m), 1.67-1.96 (9H, m),2.13- 2.23 (4H, m), 2.43 (3H, s), 2.49 (1H, tt, J = 3.5 and 11.7 Hz),2.95 (3H, s), 3.06 (3H, s), 3.90-4.02 (1H, m), 4.17 (1H, tt, J = 3.8 and11.9 Hz), 5.64-5.70 (1H, m), 7.29 (1H, s) 417

TABLE 81 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 209

colorless solid 134-136 CDCl₃ 1.22-1.34 (3H, m), 1.37-1.51 (2H, m),1.70- 1.87 (5H, m), 1.89-1.96 (2H, m), 2.13-2.23 (6H, m), 2.40-2.49 (1H,m), 2.43 (3H, s), 3.92-4.02 (1H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),5.66-5.72 (1H, m), 7.30 (1H, s) 371 210

colorless foamy solid CDCl₃ 1.21-1.33 (1H, m), 1.37-1.50 (2H, m), 1.47(9H, s), 1.69-1.95 (5H, m), 2.12-2.21 (2H, m), 2.41 (3H, s), 2.92 (3H,s), 3.47- 3.60 (4H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 7.26- 7.36(1H, m), 7.34 (1H, s) 421 211

colorless solid 130-142 DMSO-d₆ 1.17-1.30 (1H, m), 1.37-1.50 (2H, m),1.50-1.86 (5H, m), 2.02-2.10 (2H, m), 2.36 (3H, s), 2.56-2.61 (2H, m),3.03-3.12 (2H, m), 3.51- 3.57 (1H, m), 3.57 (3H, s), 4.20 (1H, tt, J =3.8 and 11.6 Hz), 7.66 (1H, s), 8.72-8.87 (3H, m) 321 212

colorless solid 153-154 CDCl₃ 1.21-1.34 (1H, m), 1.37-1.49 (2H, m),1.70-1.96 (5H, m), 2.12 (3H, s), 2.13- 2.22 (2H, m), 2.44 (3H, s), 3.08(3H, s), 3.58-3.71 (4H, m), 4.16 (1H, tt, J = 3.8 and 11.8 Hz),7.30-7.37 (1H, m), 7.31 (1H, s) 363

TABLE 82 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 213

colorless solid 120-130 DMSO-d₆ 1.14-1.28 (1H, m), 1.35-1.48 (2H, m),1.62-1.85 (5H, m), 2.01- 2.08 (2H, m), 2.35 (3H, s), 2.81 (3H, s), 2.86(3H, s), 3.18-3.23 (2H, m), 3.38-3.44 (2H, m), 4.19 (1H, tt, J = 3.8 and11.5 Hz), 7.75 (1H, s), 8.62- 8.68 (1H, m) 399 214

colorless foamy solid CDCl₃ 1.21-1.34 (1H, m), 1.28 (3H, t, J = 7.1 Hz),1.38- 1.51 (2H, m), 1.57-1.97 (7H, m), 2.01-2.08 (2H, m), 2.14- 2.21(2H, m), 2.36 (2H, dt, J = 2.3 and 11.6 Hz), 2.44 (3H, s), 2.93-3.00(2H, m), 3.24 (2H, s), 3.94-4.04 (1H, m), 4.12-4.22 (1H, m), 4.19 (2H,q, J = 7.1 Hz), 5.72- 5.77 (1H, m), 7.32 (1H, s) 433 215

colorless solid 230-236 DMSO-d₆ 1.16-130 (1H, m), 1.36-1.49 (2H, m),1.61-1.88 (7H, m), 2.01-2.08 (2H, m), 2.36 (3H, s), 2.41-2.59 (4H, m),3.07-3.14 (2H, m), 3.17-3.20 (2H, m), 3.73- 3.84 (1H, m), 4.18 (1H, tt,J = 3.9 and 11.5 Hz), 7.83 (1H, s), 8.31-8.35 (1H, m) 405 216

pale yellow solid 156-158 CDCl₃ 1.21-1.34 (1H, m), 1.29 (3H, t, J = 7.1Hz), 1.33 (6H, s), 1.37-1.69 (4H, m), 1.69-1.97 (5H, m), 2.01-2.08 (2H,m), 2.13- 2.21(2H, m), 2.31-2.41 (2H, m), 2.43 (3H, s), 2.92-2.99 (2H,m), 3.91- 4.01 (1H, m), 4.12-4.22 (1H, m), 4.19 (2H, q, J = 7.1 Hz),5.70-5.75 (1H, m), 7.30 (1H, s) 461

TABLE 83 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 217

colorless solid 251-256 DMSO-d₆ 1.16-1.30 (1H, m), 1.25 (6H, s),1.34-1.51 (2H, m), 1.62-1.86 (7H, m), 1.92-1.99 (2H, m), 2.02- 2.09 (2H,m), 2.36 (3H, s), 2.65-2.76 (2H, m), 3.13- 3.20 (2H, m), 3.81-3.91 (1H,m), 4.19 (1H, tt, J = 3.7 and 11.5 Hz), 7.86 (1H, s), 8.34-8.39 (1H, m)433 218

colorless solid 125-127 CDCl₃ 1.21-1.34 (1H, m), 1.38-1.50 (2H, m),1.72- 1.77 (5H, m), 2.14-2.22 (2H, m), 2.36-2.46 (1H, m), 2.44 (3H, s),3.60- 3.66 (2H, m), 3.83-3.88 (2H, m), 4.18 (1H, tt, J = 3.8 and 11.8Hz), 6.36-6.44 (1H, m), 7.36 (1H, s) 308 219

colorless solid 207-208 CDCl₃ 1.21-1.34 (1H, m), 1.38-1.51 (2H, m), 1.57(6H, s), 1.71-1.97 (5H, m), 2.12-2.20 (2H, m), 2.44 (3H, s), 3.72-3.77(2H, m), 3.78-3.83 (2H, m), 4.16 (1H, tt, J = 3.8 and 11.8 Hz),6.40-6.46 (1H, m), 7.31 (1H, s) 419 220

colorless solid 169-171 CDCl₃ 1.21-1.33 (1H, m), 1.37-1.48 (2H, m),1.68- 1.96 (5H, m), 2.11-2.21 (2H, m), 2.44 (3H, s), 2.94 (3H, s),3.23-3.29 (4H, m), 3.47-3.52 (2H, m), 3.58-3.64 (2H, m), 3.66-3.71 (4H,m), 4.16 (1H, tt, J = 3.8 and 11.8 Hz), 7.34 (1H, s), 7.94-7.99 (1H, m)434

TABLE 84 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 221

colorless solid 103-105 (Et₂O/ hexane) CDCl₃ 1.18-1.32 (1H, m),1.36-1.50 (2H, m), 1.68- 1.95 (5H, m), 2.12-2.20 (2H, m), 2.44 (3H, s),2.86 (6H, s), 2.90 (3H, s), 3.44-3.49 (2H, s), 3.56- 3.62 (2H, m), 4.16(1H, tt, J = 3.8 and 11.8 Hz), 7.39 (1H, s), 8.37-8.43 (1H, m) 392 222

colorless solid 109-113 (Et₂O/ hexane) CDCl₃ 1.18-1.33 (1H, m),1.36-1.50 (2H, m), 1.69- 1.96 (5H, m), 2.12-2.20 (2H, m), 2.44 (3H, s),2.96 (3H, brs), 3.46-3.64 (4H, s), 3.72 (3H, s), 4.17 (1H, tt, J = 3.8and 11.8 Hz), 6.05-6.15 (0.2H, m), 7.00-7.08 (0.8H, m), 7.32 (1H, s) 379223

colorless solid 136-137 (Et₂O/ hexane) CDCl₃ 1.18-1.33 (1H, m),1.36-1.50 (2H, m), 1.69- 1.96 (5H, m), 2.12-2.20 (2H, m), 2.44 (3H, s),2.99 (0.5H, s), 3.06 (2.5H, s), 3.41 (2.5H, s), 3.44 (0.5H, s),3.56-3.70 (4H, s), 4.10- 4.21 (3H, m), 6.65-6.72 (0.17H, m), 7.12-7.18(0.83H, m), 7.33 (1H, s) 393 224

colorless foamy solid CDCl₃ 1.21-1.34 (1H, m), 1.37-1.52 (2H, m), 1.70-1.96 (5H, m), 2.13-2.22 (2H, m), 2.43 (0.3H, s), 2.44 (2.7H, s), 2.97(2.7H, s), 3.08 (0.3H, s), 3.38-3.74 (5H, s), 4.11- 4.22 (3H, m),6.17-6.24 (0.1H, m), 6.78-6.84 (0.9H, m), 7.29 (0.9H, s), 7.34 (0.1H, s)379

TABLE 85 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 225

colorless solid 190-194 CDCl₃ 1.20-1.50 (5H, m), 1.66-1.96 (9H, m),2.12-2.26 (4H, m), 2.43 (3H, s), 2.44-2.68 (1H, m), 2.96 (0.6H, s), 3.13(2.4H, s), 3.48-3.59 (2H, m), 3.76-3.83 (2H, m), 3.91-4.03 (1H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 5.68-5.74 (1H, m), 7.30 (1H, s) 447 226

colorless solid 190-194 CDCl₃ 1.21-1.33 (1H, m), 1.37-1.50 (2H, m),1.54-1.64 (1H, m), 1.70- 1.98 (7H, m), 2.05-2.40 (5H, m), 2.43 (3H, s),2.92-3.02 (1H, m), 3.70 (3H, s), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),4.46-4.55 (1H, m), 5.77-5.84 (1H, m), 7.30 (1H, s) 390 227

colorless solid 164-167 DMSO-d₆ 1.16-1.31 (1H, m), 1.37-1.86 (10H, m),1.93-2.08 (5H, m), 2.35 (3H, s), 2.87-2.97 (1H, m), 4.18 (1H, tt, J =3.8 and 11.7 Hz), 4.23- 4.32 (1H, m), 7.81 (1H, s), 8.32-8.36 (1H, m),12.14 (1H, brs) 376 228

colorless solid >300 DMSO-d₆ 1.16-1.29 (1H, m), 1.36-1.49 (2H, m),1.62-1.86 (5H, m), 2.00-2.07 (2H, m), 2.35 (3H, s), 2.91 (3H, s), 3.39-3.58 (8H, m), 4.19 (1H, tt, J = 3.8 and 11.6 Hz), 7.69 (1H, s),8.60-8.66 (1H, m) 418

TABLE 86 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 229

colorless foamy solid CDCl₃ 1.21-1.33 (1H, m), 1.38-1.51 (2H, m), 1.58-1.68 (1H, m), 1.70-2.05 (8H, m), 2.13-2.21 (2H, m), 2.23-2.40 (2H, m),2.43 (3H, s), 2.96 (3H, s), 3.05 (3H, s), 3.12-3.22 (1H, m), 4.17 (1H,tt, J = 3.8 and 11.8 Hz), 4.43- 4.52 (1H, m), 5.83-5.89 (1H, m), 7.31(1H, s) 403 231

colorless solid 75-90 DMSO-d₆ 1.15-1.28 (1H, m), 1.36-1.48 (2H, m),1.51-1.85 (8H, m), 1.92-2.07 (5H, m), 2.36 (3H, s), 2.83 (3H, s), 3.02(3H, s), 3.18-3.29 (1H, m), 4.18 (1H, tt, J = 3.8 and 11.6 Hz),4.22-4.32 (1H, m), 7.81 (1H, s), 8.30-8.35 (1H, m) 403 231

colorless solid  95-101 CDCl₃ 1.21-1.33 (1H, m), 1.37-1.50 (2H, m),1.54-1.64 (1H, m), 1.70-1.98 (7H, m), 2.05-2.40 (5H, m), 2.43 (3H, s),2.92-3.02 (1H, m), 3.70 (3H, s), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),4.46- 4.55 (1H, m), 5.84-5.89 (1H, m), 7.31 (1H, s) 390 232

colorless solid 165-168 DMSO-d₆ 1.16-1.30 (1H, m), 1.37-1.86 (10H, m),1.93-2.09 (5H, m), 2.35 (3H, s), 2.87-2.96 (1H, m), 4.19 (1H, tt, J =3.8 and 11.7 Hz), 4.23- 4.31 (1H, m), 7.81 (1H, s), 8.32-8.36 (1H, m),12.14 (1H, brs) 376

TABLE 87 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 233

colorless foamy solid CDCl₃ 1.21-1.33 (1H, m), 1.38-1.51 (2H, m),1.59-1.68 (1H, m), 1.70-2.04 (8H, m), 2.13-2.21 (2H, m), 2.23-2.40 (2H,m), 2.43 (3H, s), 2.96 (3H, s), 3.05 (3H, s), 3.12-3.22 (1H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 4.42-4.52 (1H, m), 5.83-5.89 (1H, m),7.30 (1H, s) 403 234

colorless solid  96-105 DMSO-d₆ 1.15-1.28 (1H, m), 1.36-1.48 (2H, m),1.51-1.85 (8H, m), 1.92-2.07 (5H, m), 2.36 (3H, s), 2.83 (3H, s), 3.02(3H, s), 3.18-3.29 (1H, m), 4.18 (1H, tt, J = 3.8 and 11.6 Hz),4.22-4.31 (1H, m), 7.81 (1H, s), 8.30-8.35 (1H, m) 403 235

colorless solid 210-212 CDCl₃ 1.22-1.33 (1H, m), 1.38-1.56 (4H, m),1.70-1.96 (5H, m), 2.00-2.08 (2H, m), 2.14-2.22 (2H, m), 2.44 (3H, s),2.84 (6H, s), 2.89-2.99 (2H, m), 3.65-3.73 (2H, m), 4.08-4.22 (2H, m),5.78-5.84 (1H, m), 7.32 (1H, s) 418 236

colorless solid 235-238 CDCl₃ 1.20-1.35 (3H, m), 1.38-1.51 (2H, m),1.72-1.97 (9H, m), 2.13-2.26 (4H, m), 2.43 (3H, s), 3.49-3.54 (2H, m),3.60-3.72 (6H, m), 3.90- 4.02 (1H, m), 4.17 (1H, tt, J = 3.8 and 11.8Hz), 5.67- 5.72 (1H, m), 7.30 (1H, s) 459

TABLE 88 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 237

colorless solid >300 DMSO-d₆ 1.17-1.49 (7H, m), 1.63-1.92 (9H, m),2.01-2.11 (3H, m), 2.35 (3H, s), 2.55 (3H, d, J = 4.5 Hz), 3.59-3.71(1H, m), 4.18 (1H, tt, J = 3.8 and 11.6 Hz), 7.64-7.70 (1H, m), 7.79(1H, s), 8.22-8.27 (1H, m) 403 238

colorless solid >300 DMSO-d₆ 0.33-0.39 (2H, m), 0.56-0.62 (2H, m),1.16-1.49 (7H, m), 1.63-1.91 (9H, m), 1.96-2.08 (3H, m), 2.35 (3H, s),2.57-2.63 (1H, m), 3.60-3.72 (1H, m), 4.13-4.22 (1H, m), 7.75-7.78 (1H,m), 7.78 (1H, s), 8.21-8.26 (1H, m) 429 239

colorless solid 260-263 CDCl₃ 1.21-1.34 (3H, m), 1.37- 1.60 (4H, m),1.68-1.98 (11H, m), 2.14-2.26 (4H, m), 2.43 (3H, s), 2.48 (1H, tt, J =3.7 and 11.6 Hz), 3.15-3.31 (2H, m), 3.74-3.83 (1H, m), 3.91- 4.02 (2H,m), 4.08-4.16 (1H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 5.68-5.73(1H, m), 7.30 (1H, s) 473 240

colorless solid 230-231 CDCl₃ 1.21-1.34 (1H, m), 1.38-1.51 (2H, m),1.57-1.66 (2H, m), 1.72-1.97 (5H, m), 2.05-2.13 (2H, m), 2.15-2.23 (2H,m), 2.44 (3H, s), 2.83 (6H, s), 2.96-3.06 (2H, m), 3.72-3.80 (2H, m),4.06-4.16 (1H, m), 4.18 (1H, tt, J = 3.8 and 11.8 Hz), 5.78-5.93 (1H,m), 7.34 (1H, s) 454

TABLE 89 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 241

colorless solid 83-87 CDCl₃ 1.21-1.50 (5H, m), 1.47 (9H, s), 1.70-2.06(7H, m), 2.13-2.21 (2H, m), 2.43 (3H, s), 2.80-2.96 (2H, m), 4.04-4.17(2H, m), 4.18 (1H, tt, J = 3.9 and 11.8 Hz), 5.74- 5.81 (1H, m), 7.33(1H, s) 447 242

pale yellow solid 153-160 DMSO-d₆ 1.15-1.29 (1H, m), 1.36-1.49 (2H, m),1.62-1.86 (7H, m), 1.91-1.99 (2H, m), 2.00-2.08 (2H, m), 2.36 (3H, s),2.89-3.06 (2H, m), 3.26- 3.35 (2H, m), 3.97-4.06 (1H, m), 4.19 (1H, tt,J = 3.8 and 11.6 Hz), 7.89 (1H, s), 8.50- 8.55 (1H, m), 8.76 (1H, brs)347 243

colorless foamy solid CDCl₃ 1.22-1.33 (1H, m), 1.38-1.50 (2H, m),1.69-1.97 (6H, m), 2.13-2.22 (2H, m), 2.26-2.43 (2H, m), 2.44 (3H, s),2.58-2.64 (1H, m), 2.72- 2.77 (1H, m), 2.91-2.98 (1H, m), 3.64 and 3.65(total 2H, each s), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 6.34-6.40 (1H,m), 7.26-7.38 (6H, m) 423 244

colorless foamy solid CDCl₃ 1.21-1.34 (1H, m), 1.38-1.50 (2H, m), 1.69-1.97 (6H, m), 2.10-2.28 (3H, m), 2.42 (3H, s), 2.90- 3.02 (2H, m),3.09-3.22 (2H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 4.54- 4.63 (1H,m), 6.33-6.39 (1H, m), 7.38 (1H, m) 333

TABLE 90 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 245

colorless foamy solid CDCl₃ 1.21-1.34 (1H, m), 1.38- 1.50 (2H, m),1.71-1.96 (5H, m), 1.99-2.08 (1H, m), 2.12-2.23 (3H, m), 2.43 (3H, s),2.89 (6H, s), 3.42-3.62 (4H, m), 4.17 (1H, tt, J = 3.9 and 11.8 Hz),4.50- 4.58 (1H, m), 6.60-6.65 (1H, m), 7.35 (1H, s) 404 246

colorless solid 110-114 DMSO-d₆ 1.16-1.30 (1H, m), 1.36-1.50 (2H, m),1.62-1.91 (6H, m), 2.00-2.10 (3H, m), 2.35 (3H, s), 2.74 (6H, s), 3.21(1H, dd, J = 5.4 and 10.6 Hz), 3.29-3.47 (2H, m), 3.55 (1H, dd, J = 7.6and 10.6 Hz), 4.19 (1H, tt, J = 3.8 and 11.6 Hz), 4.28-4.36 (1H, m),7.86 (1H, s), 8.50-8.55 (1H, m) 404 247

colorless solid 251-254 CDCl₃ 1.12-1.50 (7H, m), 1.69- 1.96 (8H, m),2.07-2.21 (4H, m), 2.43 (3H, s), 3.38-3.43 (2H, m), 3.85-3.95 (1H, m),4.00 (2H, brs), 4.17 (1H, tt, J = 3.9 and 11.9 Hz), 5.21 (1H, brs),5.63- 5.69 (1H, m), 7.30 (1H, s) 458 248

pale yellow oil CDCl₃ 1.21-1.33 (1H, m), 1.28 (3H, t, J = 7.1 Hz),1.37-1.51 (2H, m), 1.70-2.06 (9H, m), 2.15-2.23 (2H, m), 2.44 (3H, s),2.57-2.67 (1H, m), 3.14-3.24 (2H, m), 4.11-4.22 (1H, m), 4.17 (2H, q, J= 7.1 Hz), 4.35- 4.45 (2H, m), 7.12 (1H, s) 404

TABLE 91 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 249

colorless solid 94-96 CDCl₃ 1.20-1.33 (1H, m), 1.37-1.50 (2H, m),1.70-1.96 (7H, m), 2.02-2.10 (2H, m), 2.12-2.20 (2H, m), 2.44 (3H, s),2.65-2.75 (1H, m), 3.17- 3.28 (2H, m), 4.18 (1H, tt, J = 3.8 and 11.9Hz), 4.36- 4.45 (2H, m), 7.13 (1H, s) 376 250

colorless solid 211-214 CDCl₃ 1.21-1.33 (1H, m), 1.37- 1.51 (2H, m),1.70-1.99 (9H, m), 2.12-2.22 (2H, m), 2.39 (1H, tt, J = 4.0 and 11.3Hz), 2.44 (3H, s), 2.84 (3H, d, J = 4.8 Hz), 3.00- 3.12 (2H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 4.48-4.57 (2H, m), 5.46-5.55 (1H, m),7.13 (1H, s) 389 251

colorless oil CDCl₃ 1.20-1.32 (1H, m), 1.26 (3H, t, J = 7.1 Hz),1.37-1.50 (2H, m), 1.55-1.66 (1H, m), 1.70- 1.97 (7H, m), 2.10-2.20 (3H,m), 2.44 (3H, s), 2.53-2.63 (1H, m), 3.12-3.21 (1H, m), 3.27-3.38 (1H,m), 4.12-4.22 (1H, m), 4.15 (2H, q, J = 7.1 Hz), 4.25-4.34 (1H, m),4.47-4.56 (1H, m), 7.16 (1H, s) 404 252

colorless solid 262-266 DMSO-d₆ 1.16-1.29 (1H, m), 1.36-1.50 (2H, m),1.62-1.92 (6H, m), 2.01-2.09 (2H, m), 2.35 (3H, s), 2.35-2.45 (1H, m),3.27-3.34 (1H, m), 3.55 (1H, dd, J = 5.5 and 11.3 Hz), 4.19 (1H, tt, J =3.8 and 11.6 Hz), 4.24-4.30 (1H, m), 4.55- 4.65 (1H, m), 7.73 (1H, s),8.52-8.56 (1H, m), 10.90 (1H, brs) 402

TABLE 92 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 253

colorless solid 221-223 DMSO-d₆ 1.16-1.28 (1H, m), 1.36-1.50 (2H, m),1.62-1.91 (6H, m), 2.00-2.08 (2H, m), 2.35 (3H, s), 2.40-2.48 (1H, m),2.87 (3H, s), 3.39 (1H, dd, J = 6.9 and 11.4 Hz), 3.58 (1H, tt, J = 5.4and 11.4 Hz), 4.19 (1H, tt, J = 3.8 and 11.6 Hz), 4.33 (1H, t, J = 8.4Hz), 4.56-4.64 (1H, m), 7.71 (1H, s), 8.51-8.56 (1H, m) 416 254

pale yellow foamy solid CDCl₃ 1.21-1.34 (1H, m), 1.37-1.49 (3H, m),1.52-1.63 (1H, m), 1.70-1.97 (8H, m), 2.12-2.20 (2H, m), 2.43 (3H, s),2.44-2.60 (1H, m), 3.26- 3.61 (4H, m), 4.05-4.17 (2H, m), 4.17 (1H, tt,J = 3.8 and 11.9 Hz), 7.18 (1H, s) 362 255

colorless solid    247-248.5 CDCl₃ 2.11-2.27 (4H, m), 2.48 (3H, s),2.97-3.16 (6H, m), 3.57 (2H, dt, J = 2.4 and 11.6 Hz), 4.11-4.18 (2H,m), 4.39-4.49 (1H, m), 7.36-7.41 (2H, m), 7.54-7.59 (2H, m), 7.65 (1H,s), 8.11 (1H, brs) 413 256

colorless solid 148-150 DMSO-d₆ 1.16-1.31 (1H, m), 1.37-1.51 (2H, m),1.62-1.88 (5H, m), 2.03-2.12 (2H, m), 2.40 (3H, s), 3.37-3.43 (2H, m),3.95-4.02 (2H, m), 4.22 (1H, tt, J = 3.8 and 11.5 Hz), 7.15 (1H, brs),8.00 (1H, dd, J = 2.6 and 9.1 Hz), 8.03 (1H, s), 8.16 (1H, d, J = 9.1Hz), 8.59 (1H, d, J = 2.6 Hz), 10.3 (1H, brs) 425

TABLE 93 properties Exam- m.p. (° C.) ple (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 257

colorless foamy solid CDCl₃ 1.21-1.59 (5H, m), 1.67-2.00 (8H, m), 2.12-2.22 (3H, m), 2.28-2.38 (1H, m), 2.43 (3H, s), 3.56 (2H, d, J = 6.8 Hz),4.17 (1H, tt, J = 3.8 and 11.9 Hz), 4.38-4.48 (1H, m), 5.82-5.86 (1H,m), 7.30 (1H, s) 362 258

colorless solid 183-185 (toluene) CDCl₃ 1.20-1.58 (6H, m), 1.69-1.96(7H, m), 2.12- 2.30 (3H, m), 2.43 (3H, s), 2.49-2.61 (1H, m), 3.50- 3.55(2H, m), 3.98 (2H, s), 4.17 (1H, tt, J = 3.8 and 11.9 Hz), 4.43-4.53(1H, m), 5.26 (1H, brs), 5.76-5.82 (1H, m), 7.29 (1H, s) 444 259

colorless solid 218-222 CDCl₃ 1.21-1.33 (1H, m), 1.37-1.51 (2H, m),1.70- 1.97 (5H, m), 2.15-2.21 (2H, m), 2.43 (3H, s), 4.18 (1H, tt, J =3.8 and 11.8 Hz), 4.63 (2H, s), 6.75-6.79 (2H, m), 7.13-7.17 (2H, m),8.28 (1H, s) 438 260

colorless solid 204-206 CDCl₃ 2.11-2.27 (4H, m), 2.48 (3H, s), 3.10 (3H,s), 3.57 (2H, dt, J = 2.4 and 11.6 Hz), 4.05 (2H, s), 4.11- 4.18 (2H,m), 4.37-4.48 (1H, m), 7.40-7.45 (2H, m), 7.50 (1H, s), 7.68 (1H, brs),7.70- 7.75 (2H, m) 454

TABLE 94 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 261

pale brown solid 252-254 (EtOH) DMSO-d₆ 1.91-2.07 (4H, m), 2.41 (3H, s),3.38- 3.44 (2H, s), 3.5 (2H, dt, J = 2.4 and 11.6 Hz), 3.95- 4.03 (4H,m), 4.47-4.57 (1H, m), 7.16 (1H, brs), 8.00 (1H, dd, J = 2.7 and 9.1Hz), 8.05 (1H, s), 8.16 (1H, d, J = 9.1 Hz), 8.60 (1H, d, J = 2.7 Hz),10.33 (1H, brs) 427 262

pale yellow solid 164-166 (iso-PrOH) CDCl₃ 1.22-1.35 (1H, m), 1.38-1.53(2H, m), 1.70- 1.97 (5H, m), 2.04-2.12 (1H, m), 2.15-2.25 (3H, m), 2.45(3H, s), 3.25-3.41 (2H, m), 3.46-3.57 (2H, m), 4.19 (1H, tt, J = 3.9 and11.8 Hz), 4.58-4.65 (1H, m), 6.53-6.59 (2H, m), 7.40-7.51 (4H, m) 425263

pale yellow solid 167-168 (hexane/ AcOEt) CDCl₃ 1.22-1.35 (1H, m),1.38-1.52 (2H, m), 1.71- 2.05 (7H, m), 2.11-2.23 (3H, m), 2.45 (3H, s),3.29- 3.39 (2H, m), 3.57-3.68 (2H, m), 4.19 (1H, tt, J = 3.9 and 11.8Hz), 4.52-4.58 (1H, m), 6.61-6.67 (1H, m), 7.10 (1H, dd, J = 2.2 and 8.7Hz), 7.42 (1H, dd, J = 2.5 and 14.8 Hz), 7.44 (1H, s), 7.52 (1H, brs)443 264

colorless solid 216-218 CDCl₃ 1.23-1.67 (5H, m), 1.72-1.98 (7H, m),2.15- 2.23 (2H, m), 2.50 (3H, s), 2.85-2.95 (2H, m), 3.31- 3.40 (2H, m),3.72-3.80 (1H, m), 4.20 (1H, tt, J = 3.8 and 11.8 Hz), 7.49-7.57 (2H,m), 7.64 (1H, s), 7.93 (1H, d, J = 1.7 Hz), 8.11- 8.17 (1H, m), 8.19(1H, brs) 503

TABLE 95 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 265

colorless solid 226-228 CDCl₃ −0.01 (6H, s), 0.80 (9H, s) 1.22-1.36 (1H,s), 1.40-1.68 (4H, m), 1.72-1.99 7H, m), 2.16-2.26 (2H, m), 2.48 (3H,s), 2.97-3.05 (2H, m), 3.15-3.25 (2H, m), 3.75-3.81 (1H, m), 4.16-4.26(1H, m), 7.53 (1H, s), 7.75-7.81 (5H, m) 617 266

colorless solid 229-233 CDCl₃ 1.24-1.55 (4H, m), 1.60-1.98 (9H, m),2.18- 2.25 (2H, s), 2.47 (3H, s), 2.35-2.93 (2H, m), 3.29- 3.38 (2H, m),3.75-3.82 (1H, m), 4.20 (1H, tt, J = 3.8 and 11.8 Hz), 7.54 (1H, s),7.73-7.81 (4H, m), 7.84 (1H, brs) 503 267

colorless solid 162-165 CDCl₃ 1.22-1.35 (1H, m), 1.38-1.55 (2H, m),1.72- 1.98 (5H, s), 2.17-2.24 (2H, m), 2.46 (3H, s), 2.86 (2H, t, J =6.5 Hz), 3.86 (2H, t J = 6.5 Hz), 4.19 (1H, tt, J = 3.9 and 11.8 Hz),7.23 (2H, d, J = 8.4 Hz), 7.47 (1H, s), 7.53 (2H, d, J = 8.4 Hz), 7.60(1H, brs) 384 268

pale yellow solid 211-213 CDCl₃ 1.43-1.47 (1H, m), 1.72-1.82 (2H, m),2.00- 2.27 (6H, m), 2.47 (3H, s), 2.81-2.91 (2H, m), 3 30- 3.37 (2H, m),3.56 (2H, dt, J = 2.4 and 11.6 Hz), 3.83- 3.91 (1H, m), 4.11-4.18 (2H,m), 4.38-4.48 (1H, m), 6.90- 7.00 (1H, m), 7.16-7.21 (1H, m), 7.45 (1H,s), 7.47- 7.52 (1H, m), 7.53 (1H, brs) 459

TABLE 96 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 269

colorless solid   205-206.5 (AcOEt/ hexane) CDCl₃ 1.19-1.33 (1H, m),1.38-1.50 (2H, m), 1.70- 1.97 (5H, m), 2.12-2.21 (2H, m), 2.34 (3H, s),2.45 (3H, s), 2.48-2.63 (4H, m), 2.88-2.96 (4H, m), 4.12-4.22 (1H m),7.37 (1H, d, J = 8.7 Hz), 7.48 (1H, s), 7.66 (1H, brs), 7.75 (1H, d, J =2.5 Hz), 7.83 (1H, dd, J = 2.5 and 8.7 Hz) 506 270

colorless solid >300 (EtOH) CDCl₃ 1.21-1.34 (1H, m), 1.47-1.50 (4H, m),1.54- 1.67 (2H, m), 1.71-1.96 (7H, m), 2.13-2.22 (4H, m), 2.43 (3H, s),3.51-3.59 (2H, m), 3.79 (1H, tt, J = 3.9 and 12.1 Hz), 3.89-4.01 (1H,m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 4.32-4.38 (2H, m), 6.08-6.12(1H, m), 7.44 (1H, s) 431 271

colorless solid 290 (dec.) (EtOH) CDCl₃ 1.20-1.50 (7H, m), 1.70-1.97(5H, m), 2.06- 2.21 (6H, m), 2.43 (3H, s), 3.40-3.50 (1H, m), 3.79 (2H,t, J = 8.5 Hz), 3.88-3.99 (1H, m), 4.17 (1H, tt, J = 3.8 and 11.9 Hz),4.25 (2H, t, J = 8.5 Hz), 5.69-5.77 (1H, m), 7.32 (1H, s) 430 272

colorless solid 268 (dec.) CD₃OD 1.24-1.56 (7H, m), 1.72-2.03 (9H, m),2.09- 2.17 (2H, m), 2.42 (3H, s), 2.44 (2H, t, J = 7.0 Hz), 2.58 (2H, t,J = 7.0 Hz), 3.6 1-3.70 (1H, m), 3.77-3.86 (1H, m), 4.18 (1H, tt, J =3.8 and 11.8 Hz), 7.66 (1H, s) 461

TABLE 97 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 273

pale brown solid >300 CDCl₃ 1.21-1.51 (5H, m), 1.61-1.97 (7H, m), 2.12-2.24 (4H, m), 2.37-2.49 (2H, m), 2.43 (3H, s), 2.67 (4H, s), 3.98-4.09(2H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 5.68-5.73 (1H, m), 7.32(1H, s) 443 274

colorless solid 279-280 (EtOH) CDCl₃ 1.21-1.50 (5H, m), 1.58-1.87 (7H,m), 1.88- 1.96 (2H, m), 2.12-2.21 (4H, m), 2.31-2.40 (2H, m), 2.43 (3H,s), 3.14 (2H, t, J = 7.5 Hz), 3.29 2H, t, J = 6.7 Hz), 3.50 (1H, tt, J =3.8 and 11.8 Hz), 3.84-3.97 (1H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),5.78-5.83 (1H, m), 7.34 (1H, s) 465 275

colorless solid 251-254 CDCl₃ 1.20-1.50 (7H, m), 1.70-1.98 (5H, m),2.03- 2.21 (6H, m), 2.42 (3H, s), 2.94 (3H, s), 3.60-3.71 (1H, m),3.88-3.99 (1H, m), 4.11 (2H, s), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),4.34-4.40 (1H, m), 5.17 (2H, s), 5.78-5.84 (1H, m), 7.29-7.41 (6H, s)566 276

colorless solid 274-276 (EtOH) CDCl₃ 1.21-1.50 (5H, m), 170-1.97 (7H,m), 2.11- 2.23 (4H, m), 2.33-2.49 (2H, m), 2.43 (3H, s), 2.98 (3H, s),3.81 (2H, s), 3.90-4.08 (2H, m), 4.17 (1H, tt, J = 3.9 and 11.9 Hz),5.63-5.75 (1H, m), 7.32 (1H, s) 458

TABLE 98 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 277

colorless solid   156-157.5 (AcOEt/ hexane) CDCl₃ 1.21-1.33 (1H, m),1.37-1.50 (2H, m), 1.69- 1.97 (5H, m), 2.12-2.21 (2H, m), 2.45 (3H, s),3.02 (3H, s), 3.61-3.69 (2H, m), 3.79-3.88 (2H, m), 3.93 (2H, s), 4.16(1H, tt, J = 3.9 and 11.8 Hz), 6.98-7.06 (1H, m), 7.34 (1H, s) 404 278

colorless solid 170-171 (AcOEt) CDCl₃ 1.21-1.33 (1H, m), 1.38-1.51 (2H,m), 1.70- 1.98 (7H, m), 2.12-2.22 (2H, m), 2.45 (3H, s), 3.04 (3H, s),3.38-3.46 (2H, m), 3.67 (2H, t, J = 6.0 Hz), 3.94 (2H, s), 4.17 (1H, tt,J = 3.9 and 11.8 Hz), 7.15-7.22 (1H, m), 7.43 (1H, s) 418 279

colorless solid >300 CDCl₃ 1.20-1.50 (7H, m), 1.69-1.96 (5H, m), 2.03-2.21 (6H, m), 2.41 (3H, s), 2.93 (3H, s), 3.44 (2H, t, J = 4.6 Hz),3.49-3.53 (1H, m), 3.58-3.69 (1H, m), 2.12- 3.80 (2H, m), 3.87-3.99 (1H,m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 4.70-4.78 (1H, m), 5.88-5.95(1H, m), 7.35 (1H, s) 462 280

colorless solid   274-276.5 (EtOH) CDCl₃ 1.20-1.68 (7H, m), 1.70-1.98(7H, m), 2.09- 2.22 (4H, m), 2.43 (3H, s), 2.79 (3H, s), 3.28 (4H, s),3.79 (1H, tt, J = 3.9 and), 3.87-3.98 (1H, m), 4.17 (1H, tt, J = 3.9 and11.8 Hz), 5.93-6.01 (1H, m), 7.36 (1H, s) 444

TABLE 99 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 281

colorless solid 98.5-99.5 CDCl₃ 1.21-1.35 (1H, m), 1.29 (3H, t, J = 7.1Hz), 1.38-1.51 (2H, m), 1,70-1.98 (5H, m), 2.12-2.22 (2H, m), 2.44 (3H,s), 2.64 (2H, t, J = 6.0 Hz), 3.67-3.76 (2H, m), 4.11-4.25 (1H, m), 4.19(2H, q, J = 7.1 Hz), 6.68-6.74 (1H, m), 7.37 (1H, s) 364 282

colorless solid 161-162 (AcOEt) CDCl₃ 1.20-1.33 (1 H, m), 1.38-1.50 (2H,m), 1.69- 1.96 (5H, m), 2.10-2.20 (2H, m), 2.42 (3H, s), 2.72 (2H, t, J= 5.9 Hz), 3.68-3.74 (2H, m), 4.18 (1H, tt, J = 3.9 and 11.9 Hz),6.68-6.74 (1H, m), 7.34 (H, s) 336 283

colorless solid   141-142.5 CDCl₃ 1.21-1.50 (3H, m), 1.51 (9H, s),1.71-1.97 (5H, m), 2.13-2.22 (2H, m), 2.44 (3H, s), 4.12 (2H, d, J = 4.8Hz), 4.17 (1H, tt, J = 3.8 and 11.9 Hz), 6.43- 6.49 (1H, m), 7.40 (1H,s), 378 284

colorless solid 194-195 (AcOEt) CDCl₃ 1.20-1.33 (1H, m), 1.38-1.51 (2H,m), 1.70- 1.98 (5H, m), 2.12-2.21 (2H, m), 2.44 (3H, s), 4.19 (1H, tt, J= 3.9 and 11.9 Hz), 4.27 (2H, d, J = 5.1 Hz), 6.55- 6.61 (1H, m), 7.45(1H, s) 322

TABLE 100 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 285

colorless solid 138.5-195.5 (AcOEt/ hexane) CDCl₃ 1.21-1.33 (1H, m),1.38-1.50 (2H, m), 1.70- 1.98 (5H, m), 2.11-2.21 (2H, m), 2.43 (3H, s),2.61 (2H, t, J = 5.5 Hz), 3.41-3.49 (2H, m), 3.60-3.71 (6H, m), 3.71-3.78 (2H, m), 4.17 (1H, tt, J = 3.9 and 11.8 Hz), 6.95- 7.02 (1H, m),7.32 (1H, s) 405 286

colorless solid 183.5-185   CDCl₃ 1.20-1.32 (1H, m), 1.37-1.51 (2H, m),1.45 (9H, s), 1.70-1.96 (5H, m), 2.12- 2.21 (2H, m), 2.42 (3H, s),3.38-3.45 (2H, m), 3.50-3.56 (2H, m), 4.17 (1H, tt, J = 3.9 and 11.8Hz), 4.97-5.03 (1H, m), 7.09-7.16 (1H, m), 7.36 (1H, s) 407 287

colorless solid 157-158 CDCl₃ 1.20-1.32 (1H, m), 1.37 1.37-1.52 (2H, m),1.70-1.97 (5H, m), 2.12-2.21 (2H, m), 2.43 (3H, s), 2.94 (2H, t, J = 5.7Hz), 3.45-3.52 (2H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 6.53- 6.61(1H, m), 7.36 (1H, s) 307 288

colorless solid 154-155 (AcOEt) CDCl₃ 1.21-1.33 (1H, m), 1.38-1.50 (2H,m), 1.69- 1.96 (5H, m), 2.11-2.20 (2H, m), 2.43 (3H, s), 2.61 2H, t, J =5.4 Hz), 2.98 (3H, s), 3.00 (3H, s), 3.70-3.78 (2H, m), 4.16 (1H, tt, J= 3.9 and 11.9 Hz), 7.10-7.17 (1H, m), 7.33 (1H, s), 363

TABLE 101 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 289

colorless solid 164.5-168 (AcOEt/ hexane) CDCl₃ 1.21-1.33 (1H, m),1.37-1.50 (2H, m), 1.56- 1.65 (2H, m), 1.70-2.20 (11H, m) 2.29 and 2.30(total 3H, each s), 2.42 and 2.43 (total 3H, each s), 2.57- 2.68 (2H,m), 2.83 and 2.85 (total 3H, each s), 2.89- 2.99 (2H, m), 3.51 (0.4H,tt, J = 4.1 and 11.6 Hz), 3.70- 3.79 (2H, m), 4.16 (1H, tt, J = 3.8 and11.8 Hz), 4.47 (0.6 H, tt, J = 4.2 and 12.2 Hz), 7.08-7.16 (1H, m), 7.32and 7.33 (total 1H, each s) 446 290

colorless solid   173-175.5 (AcOEt) CDCl₃ 1.21-1.34 (1H, m), 1.38-1.59(4H, m), 1.69- 1.98 (7H, m), 2.11-2.20 (2H, m), 2.43 (3H, s), 2.63 (2H,d, J = 5.5 Hz), 3.18-3.31 (2H, m), 3.65-3.78 (3H, m), 3.91- 4.00 (1H,m), 4.01-4.21 (2H, m), 7.03-7.10 (1H, m), 7.33 (1H, s) 419 291

colorless solid 214-215 (AcOEt) CDCl₃ 1.20-1.33 (1H, m) 1.38-1.52 (2H,m), 1.69- 1.98 (5H, m), 2.13-2.23 (2H, m), 2.44 (3H, s), 3.43- 3.52 (2H,m), 3.68-3.79 (6H, m), 4.18 (1H, tt, J = 3.9 and 11.8 Hz), 4.23 (2H, d,J = 3.9 Hz), 7.08-7.15 (1H, m), 7.44 (1H, s) 391 292

colorless solid   130-131.5 CDCl₃ 1.20-1.34 (1H, m), 1.38-1.51 (2H, m),1.70- 1.98 (5H, m), 2.13-2.22 (2H, m), 2.44 (3H, s), 3.04 (3H, s), 3.05(H, s), 4.18 (1H, tt, J = 3.9 and 11.8 Hz), 4.21 (2H, d, J = 3.9 Hz),7.11-7.18 (1H, m), 7.44 (1H, s) 349

TABLE 102 properties Ex- m.p. (° C.) ample recryst. MS(FAB) No. ChemicalStructure solvent ¹H-NMR (M + 1)⁺ 293

colorless solid 157-159 CDCl₃ 1.20-1.34 (1H, m), 1.38-1.50 (2H, m),1.70- 1.98 (5H, m), 2.13-2.22 (2H, m), 2.33 (3H, s), 2.40- 2.50 (4H, m),2.44 (3H, s), 3.46-3.51 (2H, m), 3.69- 3.75 (2H, m), 4.18 (1H, tt, J =3.9 and 11.8 Hz), 4.22 (2H, d, J = 3.9 Hz), 7.10-7.16 (1H, m), 7.44 (1H,s) 404 294

colorless solid 175-176 CDCl₃ 1.20-1.33 (1H, m), 1.39-1.50 (2H, m),1.53- 1.64 (3H, m), 1.70-199 (7H, m), 2.15-2.21 (2H, m), 2.44 (3H, s),3.21-3.31 (1H, m), 3.37-3.46 (1H, m), 3.66- 3.74 (1H, m), 3.99-4.09 (2H,m), 4.18 (1H, tt, J = 3.9 and 11.8 Hz), 4.23 (2H, d, J = 3.9 Hz),7.12-7.18 (1H, m), 7.44 (1H, s) 405 295

colorless foamy solid CDC1₃ 1.20-1.32 (1H, m), 1.38-1.50 (2H, m), 1.68-1.98 (5H, m), 2.11-2.21 (2H, m), 2.30 (3H, s), 2.36- 2.51 (4H, m), 2.43(3H, s), 2.61 (2H, t, J = 5.5 Hz), 3.42- 3.51 (2H, m), 3.61-3.69 (2H,m), 3.70-3.80 (2H, m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 7.00-7.09(1H, m), 7.33 (1H, s) 418 296

colorless 91-96 CD₃OD 1.22-1.38 (1H, m), 1.43-1.59 (2H, m), 1.72- 2.99(5H, m), 2.09-2.18 (2H, m), 2.42 (3H, s), 2.63 (3H, s), 2.74 (2H, t, J =6.7 Hz), 2.86- 3.00 (4H, m), 3.62 (2H, t, J = 6.7 Hz), 3.70-3.80 (4H,m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 6.72 (2H, s), 7.60 (1H, s) 418free

TABLE 103 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No.Chemical Structure solvent). ¹H-NMR (M + 1)⁺ 297

colorless foamy solid CDCl₃ 1.20-1.34 (1H, m), 1.38-1.50 (2H, m), 1.60-1.69 (2H, m), 1.72-2.21 (11H, m), 2.30 and 2.32 (total 3H, each s), 2.44(3H, s), 2.88 and 2.92 (total 3H, each, s), 2.90-2.99 (2H, m), 3.43-3.53 (0.4H, m), 4.12- 4.28 (3H, m), 4.47 (0.6H, tt J = 4.2 and 12.2 Hz),7.14- 7.27 (1H, m), 7.44 and 7.45 (total 1H, each s) 432 298

colorless solid   107-116.5 CD₃OD 1.23-1.38 (1H, m), 1.43-1.57 (2H, m),1.71- 2.21 (11H, m), 2.43 (3H, s), 2.83 (3H, s), 2.87 and 2.99 (total3H, each s), 3.02- 3.13 (2H, m), 3.49- 3.58 (2H, m), 4.01-4.13 (0.3H,m), 4.15-4.24 (1H, m), 4.21 and 4.31 (total 2H, each s), 4.50-4.60(0.7H, m), 6.70 (2H, s), 7.70 (1H, s) 432 (free) 299

colorless solid 182-183 (AcOEt) CDCl₃ 1.20-1.33 (1H, m), 1.36- 1.50 (2H,m), 1.69- 1.98 (5H, m), 2.11-2.21 (2H, m), 2.43 (3H, s), 3.51- 3.59 (2H,m), 3.64-3.76 (4H, m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 4.33-4.42(2H, m), 6.79- 6.87 (1H, m), 7.37 (1H, s) 377 300

colorless solid 158-160 (EtOH) CDCl₃ 1.20-1.33 (1H, m), 1.38- 1.51 (2H,m), 1.69- 1.96 (5H, m), 2.12-2.21 (2H, m), 2.37-2.48 (2H, m), 2.44 (3H,s), 3.21 (2H, t, J = 7.5 Hz), 3.34-3.42 (4H, m), 3.61-3.89 (2H, m), 4.17(1H, tt, J = 3.9 and 11.8 Hz), 6.20-6.27 (1H, m), 7.40 (1H, s) 411

TABLE 104 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No.Chemical Structure solvent) ¹H-NMR (M + H)⁺ 301

colorless foamy solid CDCl₃ 1.19-1.32 (1H, m), 1.37-1.50 (2H, m), 1.69-1.97 (5H, m), 2.09-2.11 (2H, m), 2.43 (3H, s), 2.92 (3H, s), 3.38-3.55(6H, m), 3.61-3.67 (1H, m), 3.72-3.79 (2H, m), 4.16 (1H, tt, J = 3.9 and11.8 Hz), 5.81-5.89 (1H, m), 7.43 (1H, s), 7.63-7.72 (1H, m) 408 302

colorless solid 182-183 (AcOEt) CDCl₃ 1.21-1.33 (1H, m), 1.37-1.50 (2H,m), 1.69- 1.97 (5H, m), 2.11-2.21 (2H, m), 2.44 (3H, s), 2.79 (3H, s),3.31-3.49 (6H, m), 3.54-3.61 (2H, m), 4.16 (1H, tt, J = 3.8 and 11.8Hz), 7.37-3.43 (1H, m), 7.38 (1H, s) 390 303

colorless solid 110-111 CDCl₃ 1.20-1.33 (1H, m), 1.96 (3H, t, J = 6.7Hz), 1.38- 1.51 (2H, m), 1.70-2.01 (7H, m), 2.12-2.21 (2H, m), 2.38-2.51 (2H, m), 2.44 (3H, s), 3.45-3.53 (2H, m), 4.10- 4.22 (3H, m),6.39-6.44 (1H, m), 7.32 (1H, s) 378 304

colorless solid 170-171 (AcOEt/ benzene) CDCl₃ 1.19-1.32 (1H, m),1.37-1.51 (2H, m), 1.70- 1.84 (3H, m), 1.88-2.01 (4H, m), 2.11-2.20 (2H,m), 2.28 (3H, s), 2.49 (2H, t, J = 6.4 Hz), 3.50-3.58 (2H, m), 4.18 (1H,tt, J = 3.8 and 11.9 Hz), 6.54-6.61 (1H, m), 7.30 (1H, s) 350

TABLE 105 properties Ex- m.p. (° C.) ample (recryst. MS(FA B) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 305

colorless solid 233-234 (EtOH) DMSO-d₆ 1.16-1.30 (1H, m), 1.37-1.49 (2H,m), 1.62-1.87 (5H, m), 2.00-2.09 (2H, m), 2.35 (3H, s), 3.33- 3.42 (2H,m), 3.46-3.52 (2H, m), 3.85 (2H, s), 4.18 (1H, tt, J = 3.8 and 11.6Hz),7.64 (1H, s), 8.03 (1H, s), 8.57- 8.62 (1H, m) 390 306

colorless solid 114.5-116   (AcOEt/ hexane) CDCl₃ 1.20-1.33 (1H, m),1.38-1.50 (2H, m), 1.70- 1.96 (5H, m), 1.99-2.06 (2H, m), 2.11-2.20 (2H,m), 2.43 (3H, s), 2.48-2.53 (2H, m), 2.97 (3H, s), 3.02 (3H, s),3.44-3.51 (2H, m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 7.39 (1H, s),7.49-7.56 (1H, m), 377 307

colorless solid 162-163 (AcOEt/ hexane) CDCl₃ 1.21-1.34 (1H, m),1.37-1.49 (2H, m), 1.39 (6H, s), 1.69-1.97 (5H, m), 2.12- 2.20 (2H, m),2.45 (3H, s), 2.90 (3H, s), 3.62-3.69 (2H, m), 3.80-3.86 (2H, m), 4.16(1H, tt, J = 3.8 and 11.8 Hz), 8.99-7.05 (1H, m), 7.34 (1H, s) 432 308

colorless solid 168-169 (AcOEt) CDCl₃ 1.21-1.33 (1H, m), 1.37-1.51 (2H,m), 1.70- 1.98 (5H, m), 2.12-2.20 (2H, m), 2.44 (3H, s), 3.66- 3.72 (2H,m), 3.89-3.96 (2H, m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 6.39-6.47(1H, m), 7.29 (1H, s) 407

TABLE 106 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 309

colorless solid 173-174 (AcOEt/ hexane) CDCl₃ 0.92-1.02 (4H, m),1.20-1.32 (1H, m), 1.37- 1.50 (2H, m), 1.70-1.84 (3H, m), 1.88-1.97 (2H,m), 2.11- 2.20 (2H, m), 2.42 (3H, s), 3.70 (2H, d, J = 5.1 Hz), 3.92(1H, t, J = 5.1 Hz), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 6.60 (1H, brs),7.33 (1H, s) 334 310

colorless solid 208-209 (AcOEt/ hexane) CDCl₃ 0.98-1.14 (4H, m),1.20-1.33 (1H, m), 1 38- 1.50 (2H, m), 1.69-1.99 (5H, m), 2.11-2.21 (2H,m), 2.40 (3H, s), 2.99 (3H, s), 3.73 (2H, s), 3.87 (2H, s), 4.14 (1H,tt, J = 3.9 and 11.8 Hz), 6.53 (1H, brs), 7.27 (1H, s) 430 311

colorless solid 113-114 CDCl₃ 1.20-1.33 (1H, m), 1.39-1.51 (2H, m),1.65- 1.98 (5H, m), 2.12-2.21 (2H, m), 2.44 (3H, s), 2.86- 2.92 (2H, m),3.44-3.56 (2H, m), 3.47 (2H, s), 3.76 (3H, s), 4.14 (1H, tt, J = 3.8 and11.8 Hz), 6.80-6.89 (1H, m), 7.40 (1H, s) 379 312

colorless solid 83-87 CDCl₃ 1.21-1.34 (1H, m), 1.38-1.50 (2H, m), 1.69-1.97 (5H, m), 2.12-2.21 (2H, m), 2.44 (3H, s), 3.48- 3.64 (4H, m), 3.79(3H, s), 4.06 (2H, s), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 4.93 (2H,brs), 7.31-7.42 (1H, m), 7.39 (1H, s) 422

TABLE 107 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 313

colorless solid 233-235 (EtOH) CDCl₃ 1.20-1.32 (1H, m), 1.38-1.50 (2H,m), 1.70- 1.98 (5H, m), 2.11-2.21 (2H, m), 2.42 (3H, s), 3.57- 3.70 (4H,m), 4.07 (2H, s), 4.14 (1H, tt, J = 3.9 and 11.9 Hz), 6.62-6.70 (1H, m),7.35 (1H, s), 7.97 (1H, brs) 390 314

colorless solid 207-2113 (EtOH) CDCl₃ 1.20-1.32 (1H, m) 1.37- 1.51 (2H,m), 1.45 (6H, s), 1.69-1.96 (5H, m), 2.11- 2.20 (2H, m), 2.44 (3H, s),3.64-71 (2H, m), 3.79-3.85 (2H, m), 4.16 (1H, tt J = 3.9 and 11.9 Hz,5.51 (1H, brs), 6.89-6.96 (1H, m), 7.33 (1H, s) 418 315

colorless solid 149-150 (AcOEt/ hexane) CDCl₃ 1.21-1.33 (1H, m),1.38-1.51 (2H, m), 1.70- 1.98 (5H, m), 2.13-2.21 (2H, m), 2.44 (3H, s),2.78 (3H, s), 3.31-3.48 (6H, m), 3.68-3.75 (2H, m), 4.17 (1H, tt, J =3.8 and 11.9 Hz), 6.62-6.70 (1H, m), 7.38 (1 H, s) 426 316

colorless solid 148.5-150 (AcOET/ hexane CDCl₃ 1.13 (3H, t, J = 7.2 Hz),1.20-1.33 (1H, m), 1.38-1.50 (2H, m), 1.70-1.98 (5H, m), 2.11-2.21 (2H,m), 2.44 (3H, s), 3.53 (2H, q, J = 7.2 Hz), 3.60-3.72 (4H, m), 3.99 (2H,s), 4.16 (1H, tt, J = 3.9 and 11.9 Hz), 6.57- 6.65 (1H, m), 7.33 (1H, s)418

TABLE 108 properties Ex- m.p. (° C.) ample (recryst. MS(FAB) No.Chemical Structure solvent) ¹H-NMR (M + 1)⁺ 317

colorless solid 154-155 (AcOEt/ hexane) CDCl₃ 1.20-1.33 (1H, m),1.37-1.50 (2H, m), 1.69- 1.97 (5H, m), 2.11-2.21 (2H, m), 2.44 (3H, s),2.99 (3H, s), 3.59-3.74 (4H, m), 4.01 (2H, s), 4.17 (1H, tt, J = 3.9 and11.9 Hz), 6.57-6.67 (1H, m), 7.34 (1H, s) 404 318

colorless solid 152-153 (AcOEt/ hexane) CDCl₃ 1.20-1.34 (1H, m), 1.30(3H, d, J = 6.8 Hz), 1.38-1.50 (2H, m), 1.69-1.98 (5H, m), 2.12-2.21(2H, m), 2.42 (3H, s), 2.75 (1H, t, J = 5.5 Hz), 3.61-3.68 (2H, m),3.74-3.82 (2H, m), 4.17 (1H, tt, J = 3.9 and 11.9 Hz), 4.21-4.31 (1H,m), 6.13-6.21 (1H, m), 7.35 (1H, s) 322 319

colorless solid 172.5-175   (AcOEt/ hexane) CDCl₃ 1.20-1.34 (1H, m),1.29 (3H, d, J = 6.8 Hz), 1.38-1.50 (2H, m), 1.69-1.96 (5H, m),2.11-2.20 (2H, m), 2.43 (3H, s), 3.61-3.77 (2H, m), 3.96-4.08 (2H, m),4.16 (1H, tt, J = 3.9 and 11.9 Hz), 4.36-4.48 (1H, m), 5.46 (1H, brs),6.79-6.86 (1H, m), 7.32 (1H, s) 404 320

colorless foamy solid CDCl₃ 1.21-1.33 (1H, m), 1.38- 1.50 (2H, m), 1.68-1.97 (6H, m), 2.11-2.21 (2H, m), 2.26-2.42 (2H, m), 2.44 (3H, s),2.58-2.63 (1H, m), 2.70-2.78 (1H, m), 2.90- 2.99 (1H, m), 3.59-3.69 (2H,m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 4.59-4.69 (1H, m), 6.34-6.42(1H, m), 723- 7.40 (6H, m) 423

TABLE 109 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 321

colorless solid 119-123 CDCl₃ 1.20-1.32(1H, m), 1.37-1.50(2H, m), 1.70-1.98(6H, m), 2.11-2.31(3H, m), 2.42(3H, s), 2.93- 3.04(2H, m),3.11-3.25(2H, m), 4.16(1H, tt, J = 3.9 and 11.9 Hz), 4.55-4.65(1H, m),6.48-6.55 (1H, m), 7.41(1H, s) 333 322

colorless foamy solid CDCl₃ 1.21-1.32(1H, m), 1.37-1.50(2H, m), 1.70-1.96(5H, m), 1.98-2.08(1H, m), 2.11-2.24(3H, m), 2.43(3H, s), 2.89(6H,s), 3.41-3.62(4H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 4.50-4.59(1H,m), 6.61-6.69 (1H, m), 7.35(1H, s) 404 323

colorless solid 126-128 DMSO-d₆ 1.16-1.29(1H, m), 1.38-1.50(2H, m),1.61-1.91(6H, m), 2.00-2.10(3H, m), 2.35(3H, s), 2.74(6H, s),3.19-3.25(1H, m), 3.30-3.49(2H, m), 3.51-3.60(1H, m), 4.19(1H, tt, J =3.8 and 11.6 Hz), 4.28-4.38(1H, m), 7.88(1H, s), 8.52-8.59(1H, m) 404(free) 324

colorless solid 146.5-148 CDCl₃ 1.20-1.34(1H, m), 1.30(3H, d, J = 6.8Hz), 1.38-1.50(2H, m), 1.69-1.98(5H, m), 2.12-2.21(2H, m), 2.42(3H, s),2.68-2.73(1H, m), 3.61-3.68(2H, m), 3.74-3.82(2H, m), 4.17(1H, tt, J =3.9 and 11.9 Hz), 4.21-4.31(1H, m), 6.11-6.19(1H, m), 7.35(1H, s) 322

TABLE 110 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 325

colorless solid 170-173 CDCl₃ 1.20-1.34(1H, m), 1.29(3H, d, J = 6.8 Hz),1.38-1.50(2H, m), 1.69-1.96(5H, m), 2.11-2.20(2H, m), 2.43(3H, s),3.61-3.77(2H, m), 3.96-4.08(2H, m), 4.16(1H, tt, J = 3.9 and 11.9 Hz),4.36-4.48(1H, m), 5.44(1H, brs), 6.79-6.86(1H, m), 7.32(1H, s) 404 326

colorless solid 116-117.5 CDCl₃ 1.20-1.33(1H, m), 1.26(3H, d, J = 6.3Hz), 1.38-1.51(2H, m), 1.70-1.97(5H, m), 2.12-2.21(2H, m), 2.42(3H, s),2.48-2.54(1H, m), 3.23-3.32(1H, m), 3.61-3.70(1H, m), 3.99-4.09(1H, m),4.17(1H, tt, J = 3.9 and 11.8 Hz), 6.42-6.50(1H, m), 7.37(1H, s) 322 327

colorless solid 213-215 CDCl₃ 1.20-1.34(1H, m), 1.38-1.50(2H, m),1.47(3H, d, J = 7.1 Hz), 1.69-1.97(5H, m), 2.12-2.20(2H, m), 2.44(3H,s), 3.37-3.44(1H, m), 3.98(2H, s), 4.10- 4.23(2H, m), 4.47-4.58(1H, m),5.42(1H, brs), 7.10- 7.18(1H, m), 7.36(1H, s) 404 328

colorless solid 115.5-117 CDCl₃ 1.20-1.33(1H, m), 1.26(3H, d, J = 6.3Hz), 1.38-1.51(2H, m), 1.70-1.97(5H, m), 2.12-2.21(2H, m), 2.42(3H, s),2.44-2.49(1H, m), 3.23-3.32(1H, m), 3.61-3.70(1H, m), 3.99-4.09(1H, m),4.17(1H, tt, J = 3.9 and 11.8 Hz), 6.40-6.48(1H, m), 7.37(1H, s) 322

TABLE 111 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 329

colorless solid 214-216 (AcOEt/ hexane) CDCl₃ 1.20-1.34(1H, m),1.38-1.50(2H, m), 1.47(3H, d, J = 7.1 Hz), 1.69-1.97(5H, m),2.12-2.20(2H, m), 2.44(3H, s), 3.37-3.44(1H, m), 3.98(2H, s), 4.10-4.23(2H, m), 4.47-4.58(1H, m), 5.46(1H, brs), 7.12- 7.20(1H, m),7.36(1H, s) 404 330

colorless solid 147-149.5 CDCl₃ 1.02(3H, t, J = 7.5 Hz), 1.20-1.32(1H,m), 1.38-1.51(2H, m), 1.58-1.97(7H, m), 2.12-2.21(2H, m), 2.43(3H, s),2.51-2.59(1H, m), 3.68-3.74(1H, m), 3.78-3.83(1H, m), 4.00-4.10(1H, m),4.17(1H, tt, J = 3.8 and 11.9 Hz), 6.07-6.14(1H, m), 7.36 (1H, s) 336331

colorless solid 180-183 CDCl₃ 1.03(3H, t, J = 7.5 Hz), 1.20-1.33(1H, m),1.37-1.50(2H, m), 1.55-1.97(7H, m), 2.11-2.19(2H, m), 2.43(3H, s),3.62-3.77(2H, m), 3.91-4.04(2H, m), 4.16(1H, tt, J = 3.8 and 11.8 Hz),4.25-4.37(1H, m), 5.45(1H, brs), 6.53-6.60(1H, m), 7.33(1H, s) 418 332

colorless solid 148.5-149.5 CDCl₃ 0.99-1.08(6H, m), 1.19-1.32(1H, m),1.38- 1.51(2H, m), 1.70-2.07(6H, m), 2.12-2.21(2H, m), 2.43(3H, s),2.51-2.60(1H, m), 3.77-3.83(2H, m), 3.86-3.95(1H, m), 4.17(1H, tt, J =3.9 and 11.8 Hz), 6.12-6.20(1H, m), 7.56(1H, s) 350

TABLE 112 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 333

colorless solid 180-184 CDCl₃ 1.05(6H, d, J = 6.8 Hz), 1.19-1.33(1H, m),1.38-1.51(2H, m), 1.69-2.01(6H, m), 2.10-2.20 (2H, m), 2.44(3H, s),3.59-3.80(2H, m), 3.88- 4.02(2H, m), 4.11-4.31(2H, m), 5.45(1H, brs),6.32-6.41(1H, m), 7.34(1H, s) 432 334

colorless foamy solid CDCl₃ 1.20-1.33(1H, m), 1.38-1.53(2H, m), 1.47(6H, s), 1.50(9H, s), 1.69-1.95(5H, m), 2.11-2.20 (2H, m), 2.40(3H, s),3.22(2H, d, J = 6.7 Hz), 4.16(1H, tt, J = 3.9 and 11.8 Hz),5.15-5.20(1H, m), 7.36(1H, s), 7.58(1H, brs) 435 335

colorless solid 134-136.5 CDCl₃ 1.20-1.50(3H, m), 1.43(6H, s), 1.70-1.97(5H, m), 2.11-2.20(2H, m), 2.43(3H, s), 2.83 (2H, s), 4.16(1H, tt, J =3.9 and 11.8 Hz), 6.70 (1H, brs), 7.28(1H, s) 335 336

colorless foamy solid CDCl₃ 1.21-1.32(1H, m), 1.38-1.51(2H, m), 1.55(6H,s), 1.69-1.96(5H, m), 2.10-2.19(2H, m), 2.44(3H, s), 3.66(2H, s),4.10-4.20(3H, m), 5.55(1H, brs), 7.34(1H, s), 7.74(1H, brs) 418

TABLE 113 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 337

colorless solid 141.5-143 DMSO-d₆ 1.18-1.31(1H, m), 1.34-1.51(2H, m),1.35(6H, s), 1.61-1.88(5H, m), 2.00- 2.09(2H, m), 2.35(3H, s), 3.62(2H,s), 3.98 (2H, m), 4.18(1H, tt, J = 3.8 and 11.5 Hz), 7.60(1H, s),8.01(1H, s), 8.28(1H, s) 418 (free) 338

colorless solid 145-147 CDCl₃ 0.97(6H, s), 1.20-1.33(1H, m), 1.39-1.53(2H, m), 1.70-1.98(5H, m), 2.12-2.21 (2H, m), 2.44(3H, s), 2.72(2H,s), 3.37(2H, d, J = 5.2 Hz), 4.17(1H, tt, J = 3.9 and 11.8 Hz), 7.29(1H,s), 8.48-8.53(1H, m) 349 339

colorless solid 180-182 CDCl₃ 1.00(6H, s), 1.20-1.34(1H, m), 1.38-1.50(2H, m), 1.70-1.98(5H, m), 2.12-2.21 (2H, m), 2.45(3H, s), 3.17(2H,d, J = 6.7 Hz), 3.43(2H, s), 4.09-4.13(2H, m), 4.17(1H, tt, J = 3.8 and11.8 Hz), 5.60(1H, brs), 7.44(1H, s), 7.83-7.89(1H, m) 432 340

colorless solid 153-154 CDCl₃ 0.83-0.91(1H, m), 0.94-1.00(1H, m),1.20-1.50(4H, m), 1.70-1.97(5H, m), 2.12- 2.21(2H, m), 2.42(3H, s),2.57-2.62(1H, m), 3.05-3.19(2H, m), 3.90-3.98(1H, m), 4.16 (1H, tt, J =3.9 and 11.8 Hz), 6.35(1H, brs), 7.32(1H, s) 334

TABLE 114 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 341

pale brown solid 220(dec.) DMSO-d₆ 1.16-1.32(1H, m), 1.38-1.51(2H, m),1.63-1.87(5H, m), 2.02-2.11(2H, m), 2.39(3H, s), 3.26-3.39(4H, m),3.67(2H, s), 4.16-4.26(1H, m), 6.91-6.96(2H, m), 7.56- 7.61(2H, m),8.00(1H, s), 8.01-8.03(1H, m), 10.06(1H, brs) 438 342

pale brown solid 155(dec.) CDCl₃ 2.11-2.28(4H, m), 2.47(3H, s), 3.45-3.49(2H, m), 3.52-3.61(4H, m), 3.87(2H, s), 4.12-4.18(2H, m),4.39-4.49(1H, m), 6.01 (1H, brs), 6.87-6.93(2H, m), 7.47(1H, s),7.50-7.56(2H, m), 7.58(1H, brs) 440 343

colorless solid 155.5-157 CDCl₃ 1.22-1.35(1H, m), 1.39-1.52(2H, m),1.72-1.98(5H, m), 2.16-2.24(2H, m), 2.47 (3H, s), 3.93(3H, s), 4.20(1H,tt, J = 3.8 and 11.8 Hz), 7.45(1H, t, J = 7.9 Hz), 7.50(1H, s), 7.74(1H,brs), 7.81(1H, dt, J = 7.9 and 1.3 Hz), 7.99-8.04(1H, m), 8.11-8.13(1H,m) 398 344

colorless foamy solid CDCl₃ 1.20-1.32(1H, m), 1.36-1.50(2H, m),1.71-1.96(5H, m), 2.15-2.22(2H, m), 2.42 (3H, s), 4.18(1H, tt, J = 3.8and 11.8 Hz), 7.42(1H, t, J = 7.9 Hz), 7.64(1H, s), 7.80- 7.85(1H, m),8.05-8.10(1H, m), 8.13-8.16 (1H, m) 8.30(1H, brs) 384

TABLE 115 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 345

colorless solid 226-228 CDCl₃ 1.25-1.35(1H, m), 1.39-1.52(2H, m),1.72-1.98(5H, m), 2.16-2.24(2H, m), 2.47 (3H, s), 3.02(3H, brs),3.13(3H, brs), 4.19 (1H, tt, J = 3.9 and 11.8 Hz), 7.12-7.16(1H, m),7.34-7.39(1H, m), 7.57(1H, s), 7.60(1H, brs), 7.64-7.68(1H, m), 8.15(1H,brs) 411 346

colorless solid 218-220 CDCl₃ 1.24-1.36(1H, m), 1.39-1.52(2H, m),1.72-1.98(5H, m), 2.17-2.25(2H, m), 2.47 (3H, s), 3.45-3.89(8H, m),4.15-4.25(1H, m), 7.15-7.20(1H, m), 7.38-7.43(1H, m), 7.51 (1H, s),7.59-7.64(1H, m), 7.71-7.74(1H, m), 7.81(1H, brs) 453 347

colorless solid 185-187 CDCl₃ 1.18-1.32(2H, m), 1.55-1.67(2H, m),2.04-2.33(9H, m), 2.43(3H, s), 3.55(2H, dt, J = 2.4 and 11.7 Hz),3.69(3H, s), 3.88-3.99 (1H, m), 4.09-4.16(2H, m), 4.36-4.45(1H, m),5.69-5.74(1H, m), 7.31(1H, s) 406 348

colorless solid 267-270 DMSO-d₆ 1.27-1.47(4H, m), 1.85-2.04(8H, m),2.12-2.22(1H, m), 2.33(3H, s), 3.49(2H, dt, J = 2.4 and 11.6 Hz),3.63-3.72(1H, m), 3.95-4.00(2H, m), 4.43-4.52(1H, m), 7.81 (1H, s),8.25-8.29(1H, m) 392

TABLE 116 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 349

colorless solid 232-234 CDCl₃ 1.22-1.34(2H, m), 1.69-1.90(4H, m),2.08-2.26(6H, m), 2.44(3H, s), 2.49(1H, tt, J = 3.6 and 11.6 Hz),2.94(3H, s), 3.06(3H, s), 3.55(2H, dt, J = 2.4 and 11.7 Hz), 3.90-4.03(1H, m), 4.10-4.17(2H, m), 4.36-4.46 (1H, m), 5.69-5.74(1H, m),7.31(1H, s) 419 350

colorless solid 220-222 CDCl₃ 1.20-1.35(2H, m), 1.71-1.89(4H, m),2.08-2.27(6H, m), 2.40-2.48(1H, m), 2.44 (3H, s), 3.47-3.72(10H, m),3.91-4.01(1H, m), 4.09-4.17(2H, m), 4.37-4.46(1H, m), 5.67-5.72(1H, m),7.31(1H, s) 461 351

colorless solid 255-260 DMSO-d₆ 1.17-1.53(6H, m), 1.62-2.07 (10H, m),2.36(3H, s), 2.48-2.54(1H, m), 2.91-3.03(1H, m), 3.13-3.24(1H, m),3.47-3.55(2H, m), 3.61-3.79(3H, m), 3.88-4.00(3H, m), 4.43-4.53(1H, m),4.72-7.75(1H, m), 7.83(1H, s), 8.26- 8.29(1H, m) 475 352

colorless solid 200-203 CDCl₃ 2.20-1.33(2H, m), 1.70-1.88(4H, m),2.08-2.27(6H, m), 2.31(3H, s), 2.35-2.48 (5H, m), 2.43(3H, s),3.48-3.66(6H, m), 3.90-4.02(1H, m), 4.10-4.16(2H, m), 4.36- 4.47(1H, m),5.65-5.71(1H, m), 7.31(1H, s) 474

TABLE 117 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 353

colorless solid 128-129 CDCl₃ 1.21-1.35(1H, m), 1.38-1.52(2H, m), 1.71-2.96(7H, m), 2.05-2.22(2H, m), 2.44(3H, s), 2.50- 2.59(6H, m),3.52-3.57(2H, m), 3.76-3.81(4H, m), 4.14-4.24(1H, m), 7.38(1H, s),7.67-7.73(1H, m) 391 354

colorless solid 138-138.5 CDCl₃ 1.22-1.34(1H, m), 1.37-1.51(2H, m),1.72- 1.96(5H, m), 2.14-2.21(2H, m), 2.45(3H, s), 2.49- 2.54(4H, m),2.59(2H, t, J = 5.9 Hz), 3.51-3.57 (2H, m), 3.74-3.78(4H, m), 4.17(1H,tt, J = 3.8 and 11.8 Hz), 6.50-6.55(1H, m), 7.32(1H, s) 377 355

colorless solid 122-123 CDCl₃ 1.22-1.53(5H, m), 1.59-1.66(4H, m), 1.71-1.97(5H, m), 2.14-2.22(2H, m), 2.40-2.48(4H, m), 2.45(3H, s),2.52-2.56(2H, m), 3.47-3.54(2H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz),6.73-6.79(1H, m), 7.31(1H, s) 375 356

colorless solid 175-178 DMSO-d₆ 0.90-1.03(2H, m), 1.23-1.37(3H, m),1.75-2.06(8H, m), 2.36(3H, s), 3.20-3.26(2H, m), 3.46-3.54(2H, m),3.59-3.72(1H, m), 3.94-4.01 (2H, m), 4.38-4.52(2H, m), 7.81(1H, s),8.23- 8.28(1H, m) 378

TABLE 118 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 357

colorless solid 193-195 CDCl₃ 1.02-1.27(4H, m), 1.62-1.87 (3H, m),2.06-2.25(6H, m), 2.43(3H, s), 2.46(3H, s), 3.55(2H, dt, J = 2.5 and11.7 Hz), 3.80-3.92(3H, m), 4.10-4.16(2H, m), 4.36-4.46(1H, m),5.67-5.72(1H, m), 7.30(1H, s), 7.34- 7.39(2H, m), 7.78-7.93(2H, m) 532358

colorless solid 165-167 CDCl₃ 1.01-1.28(4H, m), 1.43-1.56 (1H, m),1.84-1.95(2H, m), 2.08-2.25 (8H, m), 2.38-2.42(4H, m), 2.44(3H, s),3.55(2H, dt, J = 2.4 and 11.8 Hz), 3.68-3.73(4H, m), 3.85-3.95(1H, m),4.09-4.17(2H, m), 4.35-4.46(1H, m), 5.68-5.73(1H, m), 7.31(1H, s) 447359

pale yellow solid 158-160 CDCl₃ 1.00-1.27(4H, m), 1.36-1.50 (1H, m),1.84-1.92(2H, m), 2.06-2.17 (8H, m), 2.20(6H, s), 2.44(3H, s), 3.55(2H,dt, J = 2.4 and 11.7 Hz), 3.83-3.98(1H, m), 4.10-4.17(2H, m),4.36-4.47(1H, m), 5.68-5.73(1H, m), 7.31(1H, s) 405 360

pale yellow solid CDCl₃ 1.01-1.28(4H, m), 1.42-1.55 (1H, m),1.85-1.93(2H, m), 2.08-2.25 (8H, m), 2.09(3H, s), 2.33-2.42(4H, m),2.44(3H, s), 3.43-3.48(2H, m), 3.55(2H, dt, J = 2.3 and 11.7 Hz),3.59-3.63(2H, m), 4.10-4.17(2H, m), 4.37-4.47(1H, m), 5.70-5.75(1H, m),7.32(1H, s) 488

TABLE 119 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 361

colorless solid 224-225 DMSO-d₆ 1.92-2.10(4H, m), 2.42 (3H, s), 2.64(6H,s), 3.51(2H, dt, J = 2.4 and 11.5 Hz), 3.96-4.02 (2H, m), 4.50-4.60(1H,m), 7.44- 7.49(1H, m), 7.62-7.67(1H, m), 8.10-8.l6(1H, m), 8.17(1H, s),8.18-8.20(1H, m), 10.57(1H, brs) 449 362

colorless solid 226-227 DMSO-d₆ 1.91-2.10(4H, m), 2.42 (3H, s), 3.22(3H,s), 3.48-3.57(2H, m), 3.96-4.03(2H, m), 4.50-4.60 (1H, m), 7.64-7.68(2H,m), 8.06- 8.12(1H, m), 8.14(1H, s), 8.34(1H, brs), 10.61(1H, brs) 420363

colorless solid 181-182 CDCl₃ −0.04(6H, s), 0.77(9H, s), 2.12-2.284H,m), 2.50(3H, s), 3.37-3.43(2H, m), 3.57(2H, dt, J = 2.5 and 11.7 Hz),3.99-4.05 (2H, m), 4.12-4.18(2H, m), 4.40- 4.50(1H, m), 7.55-7.61(1H,m), 7.60(1H, s), 7.67-7.71(1H, m), 8.01-8.04(1H, m), 8.09(1H, brs),8.22-8.26(1H, m) 564 364

colorless solid 229-232 DMSO-d₆ 1.92-2.09(4H, m), 2.42 (3H, s),3.43-3.48(2H, m), 3.51 (2H, dt, J = 2.4 and 11.6 Hz), 3.66-3.74(2H, m),3.96-4.03(2H, m), 4.49-4.60(1H, m), 4.88-4.93 (1H, m), 7.59-7.67(2H, m),8.08- 8.13(1H, m), 8.14(1H, s), 8.30- 8.32(1H, m), 10.61(1H, brs) 450

TABLE 120 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 365

colorless solid 201-206 (EtOH/ (iso Pr)₂O) DMSO-d₆ 1.16-1.30(1H m),1.36-1.51(2H, m), 1.54-1.92 (9H, m), 2.02-2.10(2H, m), 2.34(6H, s),2.40(3H, s), 2.82- 2.92(2H, m), 3.25-3.33(2H, m), 3.62-3.70(1H, m),4.10- 4.25(1H, m), 7.12-7.21(1H, m), 7.39-7.45(1H, m), 7.62- 7.70(1H,m), 8.03(1H, s), 10.29 (1H, brs) 457 366

colorless solid 211-213 (iso- PrOH) DMSO-d₆ 1.16-1.31(1H, m),1.36-1.91(11H, m), 2.02-2.10 (2H, m), 2.29(3H, s), 2.40(3H, s),2.77-2.87(2H, m), 3.22-3.30 (2H, m), 3.58-3.67(1H, m), 4.15-4.26(1H, m),7.08-7.18(3H, m), 7.38-7.44(1H, m), 7.45-7.50 (2H, m), 7.61-7.69(1H, m),8.03 (1H, s), 10.29(1H, brs) 457 367

colorless solid 223-228 (Et₂O/ AcOEt) CD₃OD 1.26-1.41(1H, m), 1.46-1.60(2H, m), 1.73-2.07(7H, m), 2.12-2.28(4H, m), 2.46(3H, s), 2.70(3H,s), 3.53-3.66(2H, br), 3.74-3.91(2H, br), 4.02-4.14(1H, br), 4.22(1H,tt, J = 3.9 and 11.8 Hz), 7.60-7.66(2H, m), 7.89-7.96(2H, m), 7.91(1H,s), 10.26(1H, brs) 439 368

colorless solid 255(dec.) (EtOH/ H₂O) DMSO-d₆ 1.19-1.31(1H, m),1.39-1.52(2H, m), 1.65-1.89(7H, m), 1.96-2.13(4H, m), 2.29(3H, s),2.40(3H, s), 3.22-3.95(4H, m), 4.23(1H, tt, J = 3.8 and 11.6 Hz),7.11(2H, d, J = 8.0 Hz), 7.35- 7.66(1H, br), 7.47(2H, d, J = 8.0 Hz),7.72-7.91(2H, br), 8.07 (1H, brs), 10.38(1H, brs) 439

TABLE 121 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 369

colorless solid 226-227.5 (EtOH) CDCl₃ 1.19-1.32(2H, m), 1.36- 1.48(2H,m), 1.93-2.02(2H, m), 2.07-2.28(7H, m), 2.43(3H, s), 2.53-2.60(4H, m),3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.70-3.77 (4H, m), 3.83-3.97(1H, m),4.10-4.18(2H, m), 4.37-4.47 (1H, m), 5.70-5.77(1H, m), 7.31(1H, s) 433370

yellow solid 189-190.5 (EtOH) CDCl₃ 1.21-1.33(1H, m), 1.39- 1.51(2H, m),1.53-2.03(10H, m), 2.15-2.24(2H, m), 2.44(3H, s), 3.10-3.21(2H, m),3.88- 3.96(1H, m), 3.98-4.09(2H, m), 4.19(1H, tt, J = 3.8 and 11.8 Hz),6.69(1H, d, J = 9.1 Hz), 7.49(1H, s), 7.63 (1H, brs), 7.90(1H, dd, J =2.7 and 9.1 Hz), 8.19(1H, d, J = 2.7 Hz) 440 371

colorless solid 191-193 CDCl₃ 1.22-1.37(1H, m), 1.40- 1.56(3H, m),1.71-2.10(9H, m), 2.17-2.247(2H, m), 2.47(3H, s), 2.83-2.94(2H, m),3.31-3.41 (2H, m), 3.82-3.93(1H, m), 4.19(1H, tt, J = 3.8 and 11.8 Hz),6.71-6.68(1H, m), 7.48(1H, s), 7.67(1H, brs), 7.90-7.99(1H, m) 475 372

colorless solid 232-233 (EtOH) CDCl₃ 1.21-1.35(1H, m), 1.39- 1.52(3H,m), 1.69-2.06(9H, m), 2.13-2.23(2H, m), 2.30(3H, s), 2.45(3H, s),2.67-2.76(2H, m), 3.02-3.11(2H, m), 3.79-3.89 (1H, m), 4.19(1H, tt, J =3.8 and 11.8 Hz), 7.00(1H, d, J = 8.4 Hz), 7.32-7.41(2H, m), 7.44(1H,s), 7.56(1H, brs) 453

TABLE 122 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 373

colorless solid 255-256.5 (EtOH) CDCl₃ 1.21-1.35(1H, m), 1.39- 1.57(3H,m), 1.71-1.98(7H, m), 2.03-2.12(2H, m), 2.16-2.23 (2H, m), 2.45(3H, s),2.94-3.03 (2H, m), 3.39-3.48(2H, m), 3.86-3.97(1H, m), 4.19(1H, tt, J =3.8 and 11.8 Hz), 7.02 (1H, d, J = 8.9 Hz), 7.50(1H, s), 7.70-7.82(3H,m) 464 374

pale yellow foamy solid CDCl₃ 1.22-1.34(1H, m), 1.38- 1.57(3H, m),1.69-2.08(9H, m), 2.14-2.23(2H, m), 2.45(3H, s), 2.80-2.90(2H, m),3.21-3.31 (2H, m), 3.80-3.88(1H, m), 3.89(3H, s), 4.19(1H, tt, J = 3.8and 11.8 Hz), 7.05(1H, d, J = 8.8 Hz), 7.48(1H, s), 7.71(1H, brs),7.77(1H, dd, J = 2.6 and 8.8 Hz) 7.84(1H, d, J = 2.6 Hz) 497 375

colorless solid >300 DMSO-d₆ 1.19-1.32(1H, m), 1.39-1.51(2H, m),1.59-1.88 (7H, m), 1.93-2.02(2H, m), 2.03-2.11(2H, m), 2.40(3H, s),2.98-3.09(2H, m), 3.12- 3.21(2H, m), 3.76-3.85(1H, m), 4.23(1H, tt, J =3.8 and 11.5 Hz), 4.92(1H, d, J = 4.2 Hz), 7.70(1H, d, J = 8.8 Hz),8.08-8.14(2H, m), 8.35(1H, d, J = 2.6 Hz), 10.47 (1H, brs). 483 376

yellow solid 121-123 DMSO-d₆ 1.30-1.42(2H, m), 1.73-1.83(2H, m),1.91-2.09 (4H, m), 2.41(3H, s), 2.99- 3.10(2H, m), 3.51(2H, dt, J = 2.3and 11.6 Hz), 3.63- 3.72(1H, m), 3.91-4.03(4H, m), 4.44-4.54(1H, m),4.67 (1H, d, J = 4.2 Hz), 6.85(1H, d, J = 9.2 Hz), 7.82(1H, dd, J = 2.7and 9.2 Hz), 8.37(1H, d, J = 2.7 Hz), 10.13(1H, brs). 442

TABLE 123 properties m.p. (° C.) MS Example (recryst. (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 377

colorless solid 194-195 (EtOH) CDCl₃ 1.53-1.69(4H, m), 1.74- 1.82(2H,m), 1.97-2.25(6H, m), 2.31-2.40(2H, m), 2.44(3H, s), 2.50-2.59(1H, m),2.94-3.03 (2H, m), 3.41(2H, dt, J = 1.7 and 11.8 Hz), 3.55(2H, dt, J =2.4 and 11.6 Hz), 3.92-4.08 (3H, m), 4.10-4.18(2H, m), 4.36-4.47(1H, m),5.82-5.90 (1H, m), 7.33(1H, s) 433 378

colorless solid 268-269.5 (EtOH) DMSO-d₆ 1.19-1.50(5H, m), 1.62-1.88(7H,m), 2.03-2.12 (2H, m), 2.41(3H, s), 3.14- 3.28(2H, m), 3.61-3.80(2H, m),3.99-4.09(1H, m), 4.24 (1H, tt, J = 3.8 and 11.5 Hz), 4.77(1H, d, J =4.2 Hz), 7.58 (1H, d, J = 8.6 Hz), 8.10(1H, s), 8.24(1H, dd, J = 2.4 and8.6 Hz), 8.88(1H, d, J = 2.4 Hz), 10.58(1H, brs). 468 379

colorless solid 249-251.5 (EtOH) DMSO-d₆ 1.19-1.32(1H, m), 1.39-1.51(2H,m), 1.63-1.89 (5H, m), 2.03-2.12(2H, m), 2.41(3H, s), 3.33-3.41(2H, m),3.50-3.58(2H, m), 4.23 (1H, tt, J = 3.8 and 11.4 Hz), 4.79(1H, d, J =5.4 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.12(1H, s), 8.34(1H, dd, J = 2.4 and8.6 Hz), 8.55-8.63(1H, m), 8.95(1H, d, J = 2.4 Hz), 10.67 (1H, brs). 428380

colorless solid 207-209 DMSO-d₆ 1.19-1.32(1H, m), 1.39-1.51(2H, m),1.63-1.89 (5H, m), 2.03-2.12(2H, m), 2.19(3H, s), 2.24-2.40(4H, m),2.41(3H, s), 3.42-3.51(2H, m), 3.60-3.69(2H, m), 4.24(1H, tt, J = 3.9and 11.5 Hz), 7.61(1H, d, J = 8.6 Hz), 8.10(1H, s), 8.25 (1H, dd, J =2.5 and 8.6 Hz), 8.89(1H, d, J = 2.5 Hz), 10.60 (1H, brs). 467

TABLE 124 propeties m.p. (° C.) Example (recryst. MS (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 381

colorless solid 214-215.5 CDCl₃ 1.22-1.33 (1H, m), 1.38-1.51 (2H, m)1.71- 1.98 (5H, m), 2.15-23 (2H, m), 2.29 (6H, s), 2.43 (3H, s), 2.53(2H, t, J = 6.2 Hz), 3.52-3.60 (2H, m), 4.19 (1H, tt, J = 3.8 and 11.8Hz), 7.62 (1H, s), 8.12-8.34 (4H, m), 8.78-8.82 (1H, m) 455 382

colorless solid 252-254 DMSO-d₆ 1.18-1.32 (3H, m), 1.39-1.53 (4H, m),1.64-1.89 (9H, m), 2.02-2.12 (2H, m), 2.41 (3H, s), 3.36- 3.46 (1H, m),3.68-3.80 (1H, m), 4.24 (1H, tt, J = 3.8 and 11.5 Hz), 4.55 (1H, d, J =4.4 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.12 (1H, s), 8.30-8.38 (2H, m), 8.94(1H, d, J = 2.4 Hz), 10.67 (1H, brs), 482 383

colorless solid 197.5-199.5 CDCl₃ 1.22-1.35 (1H, m), 1.39-1.51 (2H, m),1.71- 2.08 (7H, m), 2.13-2.25 (2H, m), 2.36 (1.5H, s), 2.40 (1.5H, s),2.47 (3H, s), 2.56-2.2.70 (3H, m), 2.73- 2.83 (1H, m), 3.52-3.68 (2H,m), 3.82-3.91 (2H, m), 4.20 (1H, tt, J = 3.8 and 11.8 Hz), 7.31-7.38(1H, m), 7.76-7.87 (1H, m), 7.95 (1H, s), 8.48-8.58 (1H, m), 9.33 (1H,brs) 481 384

colorless solid 175-180 CDCl₃ 1.33-1.54 (2H, m), 1.45 (9H, s), 1.98-2.06(2H, m), 2.09-2.25 (4H, m), 2.44 (3H, s), 2.83-2.97 (2H, m), 3.51-3.61(2H, m), 4.02-4.19 (5H, m), 4.35-4.48 (1H, m), 5.82-5.89 (1H, m), 7.35(1H, s) 449

TABLE 125 propeties m.p. (° C.) Example (recryst. MS (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 385

colorless solid 205-214 CDCl₃ 1.37-1.9 (2H, m), 2.00-2.25 (6H, m), 2.44(3H, s), 2.70-2.80 (2H, m), 3.08-3.17 (2H, m), 3.55 (2H, dt, J = 2.4 and11.6 Hz), 4.00-4.19 (3H, m), 4.36-4.48 (1H, m), 5.81-5.90 (1H, m), 7.34(1H, s) 349 386

colorless solid 239-240 (EtOH) CDCl₃ 1.46-1.59 (2H, m), 2.00-2.25 (6H,m), 2.44 (3H, s), 2.83 (6H, s), 2.89-2.99 (2H, m), 3.55 (2H, dt, J = 2.4and 11.6 Hz), 3.64-3.73 (2H, m), 4.08-4.19 (3H, m), 4.37-4.47 (1H, m),5.91-5.98 (1H, m), 7.35 (1H, s) 420 387

colorless solid 214.5-217 CDCl₃ 1.37-1.60 (4H, m), 1.46 (9H, s),1.73-1.85 (2H, m), 2.01-2.25 (6H, m), 2.32-2.51 (3H, m), 2.44 (3H, s),2.63-2.76 (2H, m), 2.89-2.97 (2H, m), 3.55 (2H, dt, J = 2.4 and 11.6Hz), 3.90-4.01 (1H, m), 4.08-4.22 (4H, m), 4.36-4.48 (1H, m), 5.79-5.86(1H, m), 7.33 (1H, s) 532 388

colorless solid 180-182.5 CDCl₃ 1.36-1.59 (4H, m), 1.78-1.88 (2H, m),2.00- 2.25 (6H, m), 2.31-2.50 (3H, m), 2.44 (3H, s), 2.55- 2.65 (2H, m),2.89-2.99 (2H, m), 3.11-3.20 (2H, m), 3.55 (2H, dt, J = 2.4 and 11.6Hz), 3.90-4.01 (1H, m), 4.09-4.19 (2H, m), 4.37-4.48 (1H, m), 5.73-5.81(1H, m), 7.32 (1H, s) 432

TABLE 126 propeties m.p. (° C.) Example (recryst. MS (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 389

colorless solid 235.5-237 (EtOH) CDCl₃ 1.38-1.58 (4H, m), 1.80-1.91 (2H,m), 2.01- 2.25 (6H, m), 2.09 (3H, s), 2.30-2.40 (2H, m), 2.44 (3H, s),2.47-2.60 (2H, m), 2.87-2.94 (2H, m), 2.99-3.09 (2H, m), 3.55 (2H, dt, J= 2.4 and 11.6 Hz), 3.81-4.00 (2H, m), 4.09-4.18 (2H, m), 4.35-4.46 (1H,m), 4.62-4.70 (1H, m), 5.75-5.81 (1H, m), 7.33 (1H, s) 474 390

colorless solid 273-275.5 CDCl₃ 1.46-1.58 (2H, m), 1.60-1.72 (2H, m),1.88- 1.96 (2H, m), 2.02-2.24 (6H, m), 2.32-2.49 (3H, m), 2.44 (3H, s),2.64-2.74 (2H, m), 2.78 (3H, s), 2.88- 2.96 (2H, m), 3.55 (2H, dt, J =2.4 and 11.6 Hz), 3.81- 4.01 (3H, m), 4.10-4.18 (2H, m), 4.38-4.48 (1H,m), 5.73-5.80 (1H, m), 7.33 (1H, s) 510 391

colorless solid 141-145 CDCl₃ 1.20-1.32 (2H, m), 1.38-1.52 (2H, m), 1.46(9H, s), 1.89-1.98 (2H, m), 2.08-2.24 (6H, m), 2.28-2.38 (1H, m), 2.43(3H, s), 2.49-2.55 (4H, m), 3.39-3.47 (4H, m), 3.55 (2H, dt, J = 2.4 and11.6 Hz), 3.82-3.93 (1H, m), 4.09-4.16 (2H, m), 4.37-4.47 (1H, m),5.71-5.78 (1H, m), 7.31 (1H, s) 532 392

colorless solid 209-210.5 CDCl₃ 1.47 (9H, s), 1.54-1.80 (6H, m),1.83-1.92 (2H, m), 2.09-2.28 (5H, m), 2.45 (3H, s), 2.48-2.56 (4H, m),3.41-3.49 (4H, m), 3.56 (2H, dt, J = 2.4 and 11.6 Hz), 4.10-4.22 (3H,m), 4.37-4.48 (1H, m), 5.93-6.00 (1H, m), 7.33 (1H, s) 532

TABLE 127 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 393

colorless solid 270 (dec.) DMSO-d₆ 1.31-1.48 (2H, m), 1.55-1.71 (2H, m),1.88-2.08 (6H, m), 2.11-2.20 (2H, m), 2.36 (3H, s), 3.42- 3.80 (10H, m),3.93-4.00 (2H, m), 4.41-4.51 (1H, m), 7.84 (1H, s), 8.35-8.40 (1H, m),9.40-9.74 (2H, m), 11.79-11.91 (1H, m) 432 (free) 394

colorless solid 209-220 DMSO-d₆ 1.56-1.69 (2H, m), 1.85-2.07 (10H, m),2.38 (3H, s), 3.29-3.68 (11H, m), 3.92-4.09 (3H, m), 4.42-4.53 (1H, m),8.04 (1H, s), 8.07-8.11 (1H, m), 9.37- 10.00 (2H, m), 11.69-11.81 (1H,m) 432 (free) 395

colorless solid 255-256 (EtOH) CDCl₃ 1.20-1.32 (2H, m), 1.36-1.49 (2H,m), 1.89- 1.98 (2H, m), 2.07-2.24 (6H, m), 2.09 (3H, s), 2.28- 2.40 (1H,m), 2.43 (3H, s), 2.50-2.60 (4H, m), 3.41- 3.49 (2H, m), 3.55 (2H, dt, J= 2.4 and 11.6 Hz), 3.59- 3.66 (2H, m), 3.82-3.95 (1H, m), 4.09-4.17(2H, m), 4.35-4.47 (1H, m), 5.22-5.29 (1H, m), 7.32 (1H, s) 474 396

colorless solid 245-246.5 (EtOH) CDCl₃ 1.20-1.32 (2H, m), 1.37-1.49 (2H,m), 1.89- 1.99 (2H, m), 2.08-2.25 (6H, m), 2.30-2.40 (1H, m), 2.43 (3H,s), 2.63-2.73 (4H, m), 2.77 (3H, s), 3.19- 3.31 (4H, m), 3.55 (2H, dt, J= 2.4 and 11.6 Hz), 3.82- 3.95 (1H, m), 4.09-4.19 (2H, m), 4.37-4.47(1H, m), 5.69-5.78 (1H, m), 7.32 (1H, s) 510

TABLE 128 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 397

colorless solid 226.5-227.5 (EtOH) CDCl₃ 1.58-1.79 (6H, m), 1.81-1.92(2H, m), 2.08- 2.29 (5H, m), 2.09 (3H, s), 2.45 (3H, s), 2.48-2.60 (4H,m), (3.43-3.51 (2H, m), 3.56 (2H, dt, J = 2.4 and 11.6 Hz), (3.60-3.69(2H, m), 4.09-4.22 (3H, m), 4.38-4.48 (1H, m), 5.90-5.99 (1H, m), 7.33(1H, s) 474 398

colorless solid 198-199 (EtOH) CDCl₃ 1.43-1.57 (2H, m), 2.00-2.25 (6H,m), 2.44 (3H, s), 2.90-3.01 (2H, m) 3.24-3.31 (4H, m), 3.55 (2H, dt, J =2.5 and 11.6 Hz), 3.65-3.78 (6H, m), 4.08-4.20 (3H, m), 4.36-4.48 (1H,m), 5.80-5.87 (1H, m), 7.33 (1H, s) 462 399

colorless solid 211.5-213 (AcOEt) CDCl₃ 1.431.59 (2H, m), 2.00-1.99-1.27(6H, m), 2.30 (3H, s), 2.36-2.42 (4H, m), 2.44 (3H, s), 2.90- 3.01 (2H,m), 3.25-3.34 (4H, m), 3.55 (2H, dt, J = 2.4 and 11.6 Hz), 3.67-3.78(2H, m), 4.08-4.20 (3H, m), 4.36- 4.47 (1H, m), 5.98-6.06 (1H, m), 7.36(1H, s) 475 400

pale reddish brown solid 199-204 CDCl₃ 1.23-1.39 (2H, m), 1.41-1.53 (3H,m), 2.00- 2.24 (8H, m), 2.43 (3H, s), 3.55 (2H, dt, J = 2.4 and 11.6Hz), 3.60-3.71 (1H, m), 3.89-4.00 (1H, m), 4.09- 4.17 (2H, m), 4.36-4.47(1H, m) 5.69-5.75 (1H, m), 7.31 (1H, s) 364

TABLE 129 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 401

colorless solid 177-178.5 CDCl₃ 1.71-1.83 (2H, m), 2.09-2.25 (4H, m),2.32- 2.41 (2H, m), 2.44 (3H, s), 2.47-2.59 (4H, m), 3.56 (2H, dt, J =2.5 and 11.6 Hz), 4.09-4.18 (2H, m), 4.38-4.50 (2H, m), 5.89-5.96 (1H,m), 7.37 (1H, s) 362 402

colorless solid 199-200 (iso-PrOH) CDCl₃ 1.17 (6H, d, J = 6.3 Hz),1.19-1.31 (2H, m), 1.36- 1.49 (2H, m), 1.90-2.00 (4H, m), 2.08-2.28 (7H,m), 2.43 (3H, s), 2.70-2.78 (2H, m), 3.55 (2H, dt, J = 2.4 and 11.7 Hz),3.60-3.70 (2H, m), 3.82-3.95 (1H, m), 4.09- 4.17 (2H, m), 4.35-4.46 (1H,m), 5.66-5.72 (1H, m), 7.31 (1H, s) 461 403

colorless solid 202-208 CDCl₃ 1.19 (6H, d, J = 6.2 Hz), 1.56-1.92 (10H,m), 2.09-2.27 (5H, m), 2.45 (3H, s), 2.83-2.90 (2H, m), 3.56 (2H, dt, J= 2.4 and 11.6 Hz), 3.61-3.71 (2H, m), 4.09-4.23 (3H, m), 4.37-4.48 (1H,m), 5.91-6.00 (1H, m), 7.33 (1H, s) 461 404

colorless solid 170.5-172 (AcOEt) CDCl₃ 1.21-1.35 (1H, m), 1.39-1.52(2H, m), 1.71- 1.99 (5H, m), 2.14-2.25 (2H, m), 2.45 (3H, s), 4.19 (1H,tt, J = 3.8 and 11.8 Hz), 4.75 (2H, s), 7.27 (1H, d, J = 8.5 Hz), 7.56(1H, s), 7.88 (1H, brs), 8.19 (1H, dd, J = 2.4 and 8.5 Hz), 8.61 (1H, d,J = 2.4 Hz) 371

TABLE 130 propeties m.p. (° C.) Example (recryst. MS (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 405

colorless solid 232-233 CDCl₃ 2.10-2.26 (4H, m), 2.45 (3H, s), 3.57 (2H,dt, J = 2.5 and 11.5 Hz), 4.00 (3H, s), 4.10-4.19 (2H, m), 4.39-4.49(1H, m), 7.63 (1H, s), 8.17 (1H, d, J = 8.6 Hz) 8.20 (1H, brs), 8.53(1H, dd, J = 2.7 and 8.6 Hz), 8.71 (1H, d, J = 2.7 Hz) 401 406

colorless solid 262-264 DMSO-d₆ 1.90-2.10 (4H, m), 2.43 (3H, s), 3.51(2H, dt, J = 2.3 and 11.6 Hz), 3.93-4.03 (2H, m), 4.49-4.59 (1H, m),8.07 (1H, d, J = 8.6 Hz), 8.16 (1H, s), 8.35 (1H, dd, J = 2.3 and 8.6Hz), 9.00 (1H, d, J = 2.3 Hz), 10.74 (1H, brs), 387 407

colorless solid 258-259.5 (EtOH) DMSO-d₆ 1.20-1.32 (2H, m), 1.40-1.54(2H, m), 1.73-1.89 (4H, m), 1.91-2.10 (4H, m), 2.43 (3H, s), 3.34- 3.45(1H, m), 3.51 (2H, dt, J = 2.3 and 11.6 Hz), 3.69- 3.80 (1H, m),3.94-4.03 (2H, m), 4.49-4.58 (2H, m), 8.03 (1H, d, J = 8.7 Hz), 8.13(1H, s), 8.29-8.38 (1H, m), 8.95 (1H, d, J = 2.4 Hz), 10.67 (1H, brs),484 408

colorless solid 185-186 (AcOEt) CDCl₃ 2.10-2.27 (4H, m), 2.32 (6H, s),2.45 (3H, s), 2.58 (2H, t, J = 6.2 Hz), 3.51-3.61 (4H, m), 4.10-4.19(2H, m), 4.39-4.50 (1H, m), 7.66 (1H, s), 8.14-8.19 (1H, m), 8.20-8.31(3H, m), 8.78 (1H, d, J = 2.3 Hz) 457

TABLE 131 propeties m.p. (° C.) Example (recryst. MS (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 409

colorless solid 240-242 (AcOEt) CDCl₃ 1.60-1.73 (2H, m), 1.98-2.07 (2H,m), 2.10- 2.29 (6H, m), 2.30 (3H, s), 2.46 (3H, s), 2.78-2.88 (2H, m),3.57 (2H, dt, J = 2.5 and 11.6 Hz), 3.90-4.02 (1H, m), 4.10-4.19 (2H,m), 4.39-4.49 (1H, m), 7.62 (1H, s), 7.80- 7.87 (1H, m), 8.12-8.29 (3H,m), 8.77 (1H, d, J = 2.3 Hz) 483 410

colorlesds solid >300 DMSO-d₆ 1.41-1.66 (2H, m), 1.71-1.87 (2H, m),1.91-2.10 (4H, m), 2.01 (3H, s), 2.43 (3H, s), 2.60- 2.71 (1H, m),3.09-3.20 (1H, m), 3.51 (2H, dt, J = 2.3 and 11.6 Hz), 3.79-3.89 (1H,m), 3.96-4.10 (3H, m), 4.31- 4.40 (1H, m), 4.47-4.59 (1H, m), 8.02-8.08(1H, m), 8.14 (1H, s), 8.31-8.38 (1H, m), 8.52-8.59 (1H, m), 8.96 (1H,d, J = 2.4 Hz), 10.68 (1H, brs), 511 411

pale brown foam CDCl₃ 1.22-1.35 (1H, m), 1.39-1.51 (2H, m), 1.70- 1.98(5H, m), 2.14-2.25 (2H, m), 2.46 (3H, s), 2.49- 2.57 (4H, m), 3.64 (2H,s), 3.70-3.79 (4H, m), 4.20(1H, tt, J = 3.8 and 11.8 Hz), 7.42 (1H, d, J= 8.5 Hz), 7.53 (1H, s), 7.74 (1H, brs), 8.24 (1H, dd, J = 2.7 and 8.5Hz), 8.58 (1H, d, J = 2.7 Hz) 440 412

pale browm solid 225.5-227.5 (iso-PrOH) DMSO-d₆ 1.19-1.31 (1H, m),1.39-1.52 (2H, m, 1.63-1.89 (5H, m), 2.03-2.13 (2H, m), 2.32 (3H, s),2.41 (3H, s), 3.20-3.32 (4H, m), 3.79-3.91 (4H, m), 4.24 (1H, tt, J =3.6 and 11.5 Hz), 4.41-4.51 (2H, m), 7.55 (1H, d, J = 8.5 Hz), 8.13 (1H,s), 8.26 (1H, dd, J = 2.4 and 8.5 Hz), 9.03 (1H, d, J = 2.4 Hz), 10.29(1H, brs), 10.62 (1H, brs), 440 (free)

TABLE 132 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 413

pale yellow solid 214.5-216 (EtOH) CDCl₃ 1.22-1.35 (1H, m), 1.39-1.51(3H, m), 1.56- 1.69 (2H, m), 1.71-1.99 (7H, m), 2.16-2.29 (4H, m), 2.46(3H, s), 2.74-2.83 (2H, m), 3.63 (2H, s), 3.66- 3.76 (1H, m), 4.20 (1H,tt, J = 3.8 and 11.8 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.54 (1H, s), 7.79(1H, brs), 8.22 (1H, dd, J = 2.5 and 8.5 Hz), 8.57 (1H, d, J = 2.5 Hz)454 414

colorless solid 229-230.5 (AcOEt) CDCl₃ 1.22-1.35 (1H, m), 1.40-1.51(2H, m), 1.71- 1.99 (5H, m), 2.09 (3H, m), 2.16-2.22 (2H, m), 2.41- 2.56(4H, m), 2.46 (3H, s), 3.47-3.52 (2H, m), 3.61- 3.69 (2H, m), 3.66 (2H,s), 4.20 (1H, tt, J = 3.8 and 11.8 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.58(1H, s), 8.00 (1H, brs), 8.25 (1H, dd, J = 2.6 and 8.5 Hz), 8.60 (1H, d,J = 2.6 Hz) 481 415

colorless solid 266-268 (EtOH) CDCl₃ 1.42-1.53 (2H, m), 1.58-1.80 (4H,m), 2.07- 2.25 (6H, m), 2.33 (3H, s), 2.44 (3H, s), 2.61-2.69 (2H, m),3.15 (2H, s), 3.23-3.31 (2H, m), 3.55 (2H, dt, J = 2.3 and 11.6 Hz),3.88-4.00 (1H, m), 4.09-4.17 (2H, m), 4.37- 4.46 (1H, m), 4.51-4.61 (1H,m), 6.48-6.56 (1H, m), 7.46 (1H, s) 460 416

colorless solid 263-265 (EtOH) CDCl₃ 1.21-1.33 (1H, m), 1.37-1.52 (4H,m), 1.58- 1.98 (9H, m), 2.11-2.21 (4H, m), 2.33 (3H, s), 2.44 (3H, s),2.61-2.68 (2H, m), 3.14 (2H, s), 3.23-3.31 (2H, m), 3.88- 3.99 (1H, m),4.17 (1H, tt, J = 3.9 and 11.9 Hz), 4.49- 4.60 (1H, m), 6.21-6.29 (1H,m), 7.41 (1H, s) 458

TABLE 133 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 417

colorless solid 229.5-232 CDCl₃ 1.21-1.34 (2H, m), 1.38-1.50 (2H, m),1.91- 2.00 (2H, m), 2.09-2.26 (6H, m), 2.34-2.43 (1H, m), 2.44 (3H, s),2.71-2.79 (2H, m), 3.29 (2H, s), 3.32- 3.39 (2H, m), 3.55 (2H, dt, J =2.4 and 11.6 Hz), 3.84- 3.97 (1H, m), 4.09-4.18 (2H, m), 4.37-4.48 (1H,m), 5.71- 5.79 (1H, m), 5.94 (1H, brs), 7.32 (1H, s) 446 418

colorless solid 109-118 CDCl₃ 1.64-1.89 (8H, m), 2.09-2.26 (4H, m),2.32- 2.40 (1H, m), 2.45 (3H, s), 2.71-2.80 (2H, m), 3.26 (2H, s),3.32-3.42 (2H, m), 3.56 (2H, dt, J = 2.4 and 11.7 Hz), 4.09-4.20 (3H,m), 4.37-4.49 (1H, m), 5.93-6.01 (1H, m), 6.14 (1H, brs), 7.56 (1H, s)446 419

colorless solid 242-244 (EtOH) CDCl₃ 1.21-1.33 (2H, m), 1.36-1.49 (2H,m), 1.92- 2.01 (2H, m), 2.08-2.25 (6H, m), 2.29-2.39 (1H, m), 2.43 (3H,s), 2.73-2.81 (2H, m), 2.95 (3H, s), 3.28 (2H, s), 3.29-3.34 (2H, m),3.55 (2H, dt, J = 2.4 and 11.6 Hz), 3.83-3.97 (1H, m), 4.10-4.18 (2H,m), 4.36-4.47 (1H, m), 5.73-5.81 (1H, m), 7.33 (1H, s) 460 420

colorless solid 181-182 CDCl₃ 1.67-1.89 (8H, m), 2.09-2.25 (4H, m),2.28- 2.35 (1H, m), 2.45 (3H, s), 2.74-2.82 (2H, m), 2.98 (3H, s), 3.25(2H, s), 3.30-3.39 (2H, m), 3.56 (2H, dt, J = 2.3 and 11.6 Hz),4.09-4.21 (3H, m), 4.37-4.47 (1H, m), 5.88- 5.94 (1H, m), 7.33 (1H, s)460

TABLE 134 propeties m.p. (° C.) Example (recryst. MS (FAB) No. ChemicalStructure solvent) ¹H-NMR (M + 1)⁺ 421

colorless solid 206-208.5 CDCl₃ 1.19-1.31 (2H, m), 1.25 (3H, t, J = 7.1Hz), 1.39- 1.51 (2H, m), 1.68-1.80 (2H, m), 1.88-1.98 (4H, m), 2.08-2.39 (10H, m), 2.43 (3H, s), 2.83-2.92 (2H, m), 3.55 (2H, dt, J = 2.4and 11.7 Hz), 3.81-3.93 (1H, m), 4.09-4.18 (4H, m), 4.36-4.46 (1H, m),5.67-5.73 (1H, m), 7.31 (1H, s) 503 422

colorless foam CDCl₃ 1.26 (3H, t, J = 7.1 Hz), 1.54-4.81 (8H, m), 1.84-1.99 (4H, m), 2.05-2.34 (8H, m), 2.45 (3H, s), 2.99- 3.08 (2H, m), 3.56(2H, dt, J = 2.4 and 11.7 Hz), 4.10- 4.24 (5H, m), 4.38-4.48 (1H, m),5.95-6.01 (1H, m), 7.33 (1H, s) 503 423

colorless solid 201-202 CDCl₃ 1.19-1.31 (4H, m), 1.33-1.57 (4H, m),1.72- 1.81 (2H, m), 1.90-1.99 (2H, m), 2.09-2.28 (8H, m), 2.30- 2.39(1H, m), 2.43 (3H, s), 2.88-2.98 (2H, m), 3.50 (2H, d, J = 6.4 Hz), 3.55(2H, dt, J = 2.3 and 11.6 Hz), 3.81- 3.94 (1H, m), 4.09-4.17 (2H, m),4.37-4.48 (1H, m), 5.67- 5.74 (1H, m), 7.31 (1H, s) 461 424

colorless solid 119-122 CDCl₃ 1.21-1.33 (2H, m), 1.40-1.71 (6H, m),1.75- 1.85 (4H, m), 1.87-1.97 (2H, m), 2.00-2.28 (7H, m), 2.45 (3H, s),3.05-3.13 (2H, m), 3.48-3.60 (4H, m), 4.09- 4.17 (2H, m), 4.19-4.27 (1H,m), 4.36-4.48 (1H, m), 5.99- 6.07 (1H, m), 7.33 (1H, s) 461

TABLE 135 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 425

colorless solid 211-213.5 (EtOH) CDCl₃ 1.19-1.31 (2H, m), 1.39-1.69 (5H,m), 1.89- 1.98 (4H, m), 2.08-2.25 (6H, m), 2.30-2.40 (3H, m), 2.43 (3H,s), 2.78-2.88 (2H, m), 3.55 (2H, dt, J = 2.4 and 11.7 Hz), 3.62-3.75(1H, m), 3.82-3.93 (1H, m), 4.09- 4.17 (2H, m), 4.37-4.47 (1H, m),5.69-5.76 (1H, m), 7.31 (1H, s) 447 426

colorless solid 234.5-237 (EtOH) CDCl₃ l.62-1.78 (8H, m), 1.79-1.91 (4H,m), 1.98- 2.07 (2H, m), 2.09-2.26 (5H, m), 2.46 (3H, s), 2.47- 2.55 (1H,m), 2.95 (3H, s), 3.06 (3H, s), 3.10-3.18 (2H, m), 3.56 (2H, dt, J = 2.4and 11.7 Hz), 4.09-4.21 (3H, m), 4.38- 4.46 (1H, m), 5.98-6.06 (1H, m),7.36 (1H, s) 502 427

colorless solid 211-218 DMSO-d₆ 1.32-1.49 (2H, m), 1.53-1.69 (2H, m),1.88- 2.21 (12H, m), 2.36 (3H, s), 2.49-2.61 (1H, m), 2.89- 3.06 (2H,m), 3.11-3.22 (1H, m), 3.30-3.54 (4H, m), 3.64- 3.77 (1H, m), 3.91-4.00(2H, m), 4.40-4.52 (1H, m), 7.87 (1H, s), 8.40-8.49 (1H, m), 10.50-10.74(1H, m), 475 (free) 428

colorless solid 233.5-234.5 (AcOEt/EtOH) CDCl₃ 1.19-1.31 (2H, m),1.39-1.52 (2H, m), 1.68- 1.98 (6H, m), 2.07-2.51 (10H, m), 2.43 (3H, s),2.90- 2.99 (2H, m), 2.94 (3H, s), 3.05 (3H, s), 3.55 (2H, dt, J = 2.3and 11.6 Hz), 3.81-3.94 (1H, m), 4.09-4.18 (2H, m), 4.35- 4.47 (1H, m),5.71-5.79 (1H, m), 7.32 (1H, s) 502

TABLE 136 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 429

pale reddish brown viscous solid CDCl₃ 1.89-2.02 (2H, m), 2.49-2.61 (2H,m), 2.76- 2.88 (2H, m), 4.21-4.40 (2H, m), 7.40-7.59 (3H, m), 7.71- 7.90(2H, m), 8.70-8.91 (1H, m) 219 430

colorless solid 127-130.5 CDCl₃ 1.49-1.65 (2H, m), 1.76-1.88 (1H, m),1.92- 2.03 (1H, m), 3.05-3.13 (1H, m), 3.39-3.46 (1H, m), 3.49- 3.58(1H, m), 3.72-3.80 (1H, m), 3.87-3.95 (1H, m), 7.41- 7.49 (2H, m),7.50-7.59 (1H, m), 7.63 (1H, brs), 7.71- 7.80 (2H, m) 221 431

pale brown solid 170-181 CDCl₃ 1.71-1.81 (2H, m), 1.91-2.01 (2H, m),2.09 (3H, s), 3.20 (2H, s), 3.33-3.42 (1H, m), 3.56 (1H, t, J = 10.7Hz), 3.84-3.94 (2H, m), 4.15-4.25 (1H, m) 183 432

colorless solid 124-129 CDCl₃ 1.80-1.90 (2H, m), 2.07-2.15 (1H, m),2.19- 2.30 (1H, m), 2.45 (3H, s), 3.41-3.51 (1H, m), 3.72 (1H, t, J =10.7 Hz), 3.94-4.01 (2H, m), 4.39-4.49 (1H, m), 9.89 (1H, s) 229

TABLE 137 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 433

pale yellow oil CDCl₃ 1.38 (3H, t, J = 7.1 Hz), 1.72-1.90 (2H, m), 2.18-2.31 (2H, m), 2.45 (3H, s), 3.60 (1H, ddd, J = 3.4 and 9.6 and 11.5 Hz),3.82 (1H, dd, J = 8.7 and 11.3 Hz), 3.89- 3.96 (1H, m), 4.11-4.18 (1H,m), 4.32-4.40 (3H, m), 7.69 (1H, s) 295 434

colorless solid 174-176 DMSO-d₆ 1.59-1.78 (2H, m), 2.05-2.22 (2H, m),2.38 (3H, s), 3.49-3.58 (1H, m), 3.70-3.81 (2H, m), 4.00 (1H, dd, J =3.4 and 11.4 Hz), 4.32-4.40 (1H, m), 7.76 (1H, s), 13.10 (1H, brs) 267435

colorless solid 211.5-212.5 (EtOH) CDCl₃ 1.20-1.31 (2H, m), 1.36-1.49(2H, m), 1.70- 1.90 (2H, m), 1.93-2.02 (2H, m), 2.13-2.31 (5H, m), 2.43(3H, s), 2.53-2.61 (4H, m), 3.54-3.63 (1H, m), 3.69- 3.75 (4H, m), 3.81(1H, dd, J = 8.7 and 11.3 Hz), 3.84- 3.95 (2H, m), 4.10-4.16 (1H, m),4.31-4.40 (1H, m), 5.69- 5.76 (1H, m), 7.31 (1H, s) 433 436

colorless solid 223-225 (EtOH) CDCl₃ 1.14 (3H, t, J = 7.2 Hz), 1.20-1.33(2H, m), 1.35- 1.49 (2H, m), 1.92-2.02 (2H, m), 2.08-2.38 (7H, m), 2.43(3H, s), 2.72-2.81 (2H, m), 3.27 (2H, s), 3.29- 3.36 (2H, m), 3.43 (2H,q, J = 7.2 Hz), 3.55 (2H, dt, J = 2.4 and 11.6 Hz), 3.83-3.97 (1H, m),4.09-4.20 (2H, m), 4.37-4.48 (1H, m), 5.76-5.83 (1H, m), 7.33 (1H, s)474

TABLE 138 propeties Example m.p. (° C.) MS (FAB) No. Chemical Structure(recryst. solvent) ¹H-NMR (M + 1)⁺ 437

colorless solid 187-190 CDCl₃ 1.16 (3H, t, J = 7.2 Hz), 1.65-1.90 (8H,m), 2.08- 2.35 (5H, m), 2.45 (3H, s), 2.72-2.83 (2H, m), 3.24 (2H, s),3.30-3.39 (2H, m), 3.45 (2H, q, J = 7.2 Hz), 3.56 (2H, dt, J = 2.5 and11.6 Hz), 4.08-4.21 (3H, m), 4.37-4.47 (1H, m), 5.37-5.94 (1H, m), 7.33(1H, s) 474 438

colorless solid 180-186 CDCl₃ 1.01-1.29 (4H, m), 1.14 (3H, t, J = 7.2Hz), 1.40- 1.53 (1H, m), 1.86-1.94 (2H, m), 2.07-2.27 (8H, m), 2.43 (3H,s), 2.62-2.69 (2H, m), 3.08 (2H, s), 3.29- 3.33 (2H, m), 3.43 (2H, q, J= 7.2 Hz), 3.55 (2H, dt, J = 2.4 and 11.6 Hz), 3.82-3.98 (1H, m),4.09-4.18 (2H, m), 4.36-4.47 (1H, m), 5.75-5.81 (1H, m), 7.33 (1H, s)488 439

colorless solid 194-197 CDCl₃ 1.01-1.30 (4H, m), 1.40-1.54 (1H, m),1.83- 1.95 (2H, m), 2.07-2.29 (8H, m), 2.44 (3H, s), 2.51- 2.60 (2H, m),2.96 (3H, s), 3.09 (2H, s), 3.29-3.38 (2H, m), 3.55 (2H, dt, J = 2.3 and11.6 Hz), 3.84-3.98 (1H, m), 4.09-4.19 (2H, m), 4.36-4.48 (1H, m)5.78-5.86 (1H, m), 7.33 (1H, s) 474 440

pale yellow solid 255 (dec.) (iso-PrOH) DMSO-d₆ 1.90-2.08 (4H, m), 2.30(3H, s), 2.42 (3H, s), 2.93 (3H, brs), 3.51 (2H, dt, J = 2.3 and 11.7Hz), 3.50- 4.07 (8H, m), 4.47-4.57 (1H, m), 7.31-7.36 (2H, m), 7.76-7.81 (2H, m), 8.10 (1H, s), 10.36 (1H, brs) 454

Industrial Applicability

The present invention provides thienopyrazole derivatives havingselective PDE 7 (phosphodiesterase VII) inhibiting effect. Thesecompounds are effective compounds for treating various kinds of diseasessuch as allergic diseases, inflammatory diseases and immunologicdiseases.

The invention claimed is:
 1. A compound of formula (II), selected fromthe group consisting of: ethyl[(1-cyclohexyl-4-formyl-3-methyl-1H-pyrazol-5-yl)sulfanyl]-acetate,ethyl[(1-cyclopentyl-4-formyl-3-methyl-1H-pyrazol-5-yl)sulfanyl]-acetate, and5-[(4-bromobenzyl)sulfanyl]-1-cyclohexyl-3-methyl-1H-pyrazole-4-carboxaldehyde,or pharmaceutically acceptable salts thereof.